External beam radiation dose escalation for high grade glioma

  • Review
  • Intervention

Authors


Abstract

Background

The incidence of high grade glioma (HGG) is approximately 5 per 100,000 person-years in Europe and North America.

Objectives

To assess the effects of postoperative external beam radiation dose escalation in adults with HGG.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 9), MEDLINE (1977 to October 2015) and Embase (1980 to end October 2015) for relevant randomised phase III trials.

Selection criteria

We included adults with a pathological diagnosis of HGG randomised to the following external beam radiation regimens.

1. Daily conventionally fractionated radiation therapy versus no radiation therapy.
2. Hypofractionated radiation therapy versus daily conventionally fractionated radiation therapy.
3. Hyperfractionated radiation therapy versus daily conventionally fractionated radiation therapy.
4. Accelerated radiation therapy versus daily conventionally fractionated radiation therapy.

Data collection and analysis

The primary outcomes were overall survival and adverse effects. The secondary outcomes were progression-free survival and quality of life. We used the standard methodological procedures expected by Cochrane. We used the GRADE approach, as outlined by Cochrane, to interpret the overall quality of the evidence from included studies.

Main results

We included 11 randomised controlled trials (RCTs) with a total of 2062 participants and 1537 in the relevant arms for this review. There was an overall survival benefit for HGG participants receiving postoperative radiotherapy compared to the participants receiving postoperative supportive care. For the four pooled RCTs (397 participants), the overall hazard ratio (HR) for survival was 2.01 (95% confidence interval (CI) 1.58 to 2.55, P < 0.00001), moderate GRADE quality evidence favouring postoperative radiotherapy. Although these trials may not have completely reported adverse effects, they did not note any significant toxicity attributable to radiation. Progression free survival and quality of life could not be pooled due to lack of data.

Overall survival was similar between hypofractionated versus conventional radiotherapy in five trials (943 participants), where the HR was 0.95 (95% CI 0.78 to 1.17, P = 0.63), very low GRADE quality evidence. The trials reported that hypofractionated and conventional radiotherapy were well tolerated with mild acute adverse effects. These trials only reported one patient in the hypofractionated arm developing symptomatic radiation necrosis that required surgery. Progression free survival and quality of life could not be pooled due to the lack of data.

Overall survival was also similar between hypofractionated versus conventional radiotherapy in the subset of two trials (293 participants) which included 60 years and older participants with glioblastoma. For this category, the HR was 1.16 (95% CI 0.92 to 1.46, P = 0.21), high GRADE quality evidence.

There were two trials which compared hyperfractionated radiation therapy versus conventional radiation and one trial which compared accelerated radiation therapy versus conventional radiation. However, the results could not be pooled.

The conventionally fractionated radiation therapy regimens were 4500 to 6000 cGy given in 180 to 200 cGy daily fractions, over 5 to 6 weeks.

All these trials generally included participants with World Health Organization (WHO) performance status from 0 to 2 and Karnofsky performance status of 50 and higher.

The risk of selection bias was generally low among these randomized trials. The number of participants lost to follow-up for the outcome of overall survival was low. Attrition, performance, detection and reporting bias for the outcome of overall survival was low. There was unclear attrition, performance, detection and reporting bias relating to the outcomes of adverse effects, progression free survival and quality of life.

Authors' conclusions

Postoperative conventional daily radiotherapy improves survival for adults with good performance status and HGG as compared to no postoperative radiotherapy.

Hypofractionated radiation therapy has similar efficacy for survival as compared to conventional radiotherapy, particularly for individuals aged 60 and older with glioblastoma.

There is insufficient data regarding hyperfractionation versus conventionally fractionated radiation (without chemotherapy) and for accelerated radiation versus conventionally fractionated radiation (without chemotherapy).

There are HGG subsets who have poor prognosis even with treatment (e.g. glioblastoma histology, older age and poor performance status). These poor prognosis HGG individuals have generally been excluded from the randomised trials based on poor performance status. No randomised trial has compared comfort measures or best supportive care with an active intervention using radiotherapy or chemotherapy in these poor prognosis patients.

Resumen

Aumento de la dosis de radiación de haz externo para el glioma de alto grado

Antecedentes

La incidencia de glioma de alto grado (GAG) es aproximadamente cinco por 100 000 personas-año en Europa y Norteamérica.

Objetivos

Evaluar los efectos del aumento de la dosis de radiación de haz externo posoperatoria en adultos con GAG.

Métodos de búsqueda

Se hicieron búsquedas de ensayos aleatorios de fase III relevantes en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) (CENTRAL) (2015, número 9), MEDLINE (1977 hasta octubre 2015) y en Embase (1980 hasta el final de octubre 2015).

Criterios de selección

Se incluyeron adultos con diagnóstico patológico de GAG asignados al azar a los siguientes regímenes de radiación de haz externo.

1. Radioterapia convencional fraccionada diaria versus ninguna radioterapia.
2. Radioterapia hipofraccionada versus radioterapia convencional fraccionada diaria.
3. Radioterapia hiperfraccionada versus radioterapia convencional fraccionada diaria.
4. Radioterapia acelerada versus radioterapia convencional fraccionada diaria.

Obtención y análisis de los datos

Los resultados primarios fueron supervivencia general y efectos adversos. Los resultados secundarios fueron supervivencia sin progresión y calidad de vida. Se utilizaron los procedimientos metodológicos estándar previstos por Cochrane. Se utilizó el enfoque GRADE, como indica Cochrane, para interpretar la calidad general de las pruebas de los estudios incluidos.

Resultados principales

Se incluyeron 11 ensayos controlados aleatorios (ECA) con un total de 2062 participantes y 1537 en los brazos relevantes para esta revisión. Hubo un efecto beneficioso en la supervivencia general en los participantes con GAG que recibieron radioterapia posoperatoria en comparación con los participantes que recibieron tratamiento médico de apoyo posoperatorio. En los cuatro ECA agrupados (397 participantes), el cociente de riesgos instantáneos (CRI) general para la supervivencia fue 2,01 (intervalo de confianza [IC] del 95%: 1,58 a 2,55; p < 0,00001), y las pruebas de calidad moderada según GRADE favorecieron la radioterapia posoperatoria. Aunque es posible que estos ensayos no hayan informado completamente los efectos adversos, no observaron toxicidades significativas atribuibles a la radiación. No fue posible agrupar la supervivencia sin progresión y la calidad de vida debido a la falta de datos.

La supervivencia general fue similar entre la radioterapia hipofraccionada y la convencional en cinco ensayos (943 participantes), en los que el CRI fue 0,95 (IC del 95%: 0,78 a 1,17; p = 0,63), pruebas de calidad muy baja según GRADE. Los ensayos informaron que la radioterapia hipofraccionada y la convencional se toleraron bien, con efectos adversos agudos leves. Estos ensayos sólo informaron que un paciente del brazo de radioterapia hipofraccionada desarrolló necrosis sintomática por radiación que requirió cirugía. No fue posible agrupar la supervivencia sin progresión y la calidad de vida debido a la falta de datos.

La supervivencia general también fue similar entre la radioterapia hipofraccionada y la convencional en el subgrupo de dos ensayos (293 participantes) que incluyó participantes con 60 años y más con glioblastoma. En esta categoría, el CRI fue 1,16 (IC del 95%: 0,92 a 1,46; p = 0,21), pruebas de calidad alta según GRADE.

Hubo dos ensayos que compararon radioterapia hiperfraccionada con radiación convencional y un ensayo que comparó radioterapia acelerada versus radiación convencional. Sin embargo, no fue posible agrupar los resultados.

Los regímenes de radioterapia convencional fraccionada fueron de 4500 a 6000 cGy administrados en fracciones diarias de 180 a 200 cGy, durante cinco a seis semanas.

Todos estos ensayos incluyeron en general participantes con estado funcional 0 a 2 de la Organización Mundial de la Salud (OMS) y estado funcional de Karnofsky de 50 y más.

En general el riesgo de sesgo de selección fue bajo en estos ensayos aleatorios. El número de participantes perdidos del seguimiento para el resultado supervivencia general fue bajo. En general el sesgo de desgaste, rendimiento, detección e informe para el resultado de la supervivencia general fue bajo. Hubo sesgo incierto de deserción, realización, detección e informe con respecto a los resultados efectos adversos, supervivencia sin progresión y calidad de vida.

Conclusiones de los autores

La radioterapia convencional diaria posoperatoria mejora la supervivencia en los adultos con buen estado funcional y GAG en comparación con ninguna radioterapia posoperatoria.

La radioterapia hipofraccionada tiene una eficacia similar en la supervivencia en comparación con la radioterapia convencional, en especial en los individuos de 60 años de edad y más con glioblastoma.

No hay datos suficientes con respecto al hiperfraccionamiento versus la radiación convencional fraccionada (sin quimioterapia) ni para la radiación acelerada versus la radiación convencional fraccionada (sin quimioterapia).

Hay subgrupos de GAG que tienen un pronóstico deficiente incluso con tratamiento (p.ej. histología del glioblastoma, edad más avanzada y estado funcional deficiente). En general estos individuos con GAG y pronóstico deficiente se han excluido de los ensayos aleatorios debido al estado funcional deficiente. Ningún ensayo aleatorio ha comparado las medidas de comodidad o el mejor tratamiento médico de apoyo con una intervención activa con el uso de radioterapia o quimioterapia en estos pacientes de pronóstico deficiente.

Plain language summary

Radiation dose escalation for malignant glioma

Background:
High grade glioma (HGG) is a rapidly growing brain tumour in the supporting cells of the nervous system, with several subtypes such as glioblastoma (grade IV astrocytoma), anaplastic (grade III) astrocytoma and anaplastic (grade III) oligodendroglioma. It affects about 5 in 100,000 people per year in Europe and North America. A number of studies have investigated the best strategy to give radiation for people with HGG, so there is a need to look at these studies closely to see what they say. Due to toxicity, radiation is not given all in one day. In order to balance toxicity and tumour control, smaller doses of radiation are given over several days.

Conventional radiation therapy involves giving daily radiation of 180 to 200 cGy per day. Hypofractionated radiation therapy refers to the use of a higher daily dose of radiation (> 200 cGy per day) which typically reduces the overall number of fractions and therefore the overall treatment time.

Hyperfractionated radiation therapy refers to the use of a lower daily dose of radiation (< 180 cGy per day), a greater number of fractions and multiple fractions delivered per day in order to deliver a total dose at least equivalent to external beam daily conventionally fractionated radiation therapy in the same time frame. The aim with this approach is to reduce the potential for late toxicity.

Accelerated radiation therapy refers to the delivery of multiple fractions per day using daily doses of radiation consistent with external beam daily conventionally fractionated radiation therapy doses. The aim is to reduce the overall treatment time; typically, two or three fractions per day may be delivered with a six to eight hour gap between fractions.

The aim of the review:
To examine the effectiveness and safety of external beam radiation dose escalation in newly diagnosed people with HGG.

What are the main findings?
We found 11 trials (1537 participants in the relevant arms for this review) that met the criteria for our review. People with a poor prognosis generally were not eligible for entry into the randomised trials based on their poor level of health. There was an overall survival benefit for HGG participants receiving postoperative conventional radiotherapy compared to the participants receiving supportive care after surgery. Hypofractionated radiation therapy has similar efficacy for survival as compared to conventional radiotherapy, particularly for individuals aged 60 and older with glioblastoma. There were no clear differences in side effects (adverse effects) between these different treatment groups. There was insufficient data regarding other outcomes, namely progression-free survival and quality of life between these different treatment groups.

There is insufficient data regarding the outcomes of survival, adverse effects, progression free survival and quality of life for hyperfractionation versus conventionally fractionated radiation and for accelerated radiation versus conventionally fractionated radiation.

Quality of the Evidence:

The quality of the evidence ranged from very low to high. Some of the trials were at a higher risk of bias due to missing details regarding how they divided participants into treatment groups, how many patients were lost to follow-up and possible selective reporting of outcomes such as adverse effects.

Only 5 out of the 11 included trials were published after the year 2000. The majority of the trials included in the meta-analysis were published before 2000 and are now out of date. These older trials did not distinguish between the various subtypes of HGG, and they used outdated radiotherapy techniques such as whole brain radiotherapy rather than local radiotherapy (targeted only to the tumour and not the whole brain).

What are the conclusions?
Postoperative conventional daily radiotherapy improves survival for adults with good functional well-being and HGG compared to no postoperative radiotherapy.

Hypofractionated radiation therapy has similar efficacy for survival as compared to conventional radiotherapy, particularly for individuals aged 60 and older with glioblastoma.

Resumen en términos sencillos

Aumento de la dosis de radiación para el glioma maligno

Antecedentes:
El glioma de alto grado (GAG) es un tumor cerebral de crecimiento rápido en las células de apoyo del sistema nervioso, y existen varios subtipos como el glioblastoma (astrocitoma grado IV), el astrocitoma anaplásico (grado III) y el oligodendroglioma anaplásico (grado III). Afecta a cerca de cinco de 100 000 personas por año en Europa y Norteamérica. Varios estudios han investigado la mejor estrategia para administrarles radiación a los pacientes con GAG, por lo que es necesario examinar cuidadosamente estos estudios para determinar lo que dicen. La radiación no se administra toda en un día debido a su toxicidad. Para equilibrar la toxicidad y el control tumoral, se administran dosis más pequeñas de radiación durante varios días.

La radioterapia convencional incluye administrar una dosis de radiación de 180 a 200 cGy por día. La radioterapia hipofraccionada se refiere al uso de una dosis diaria mayor de radiación (> 200 cGy por día), lo que habitualmente reduce el número general de fracciones y, por lo tanto, el tiempo general de tratamiento.

La radioterapia hiperfraccionada se refiere al uso de una dosis diaria inferior de radiación (< 180 cGy por día), un mayor número de fracciones y fracciones múltiples administradas por día para aplicar una dosis total equivalente al menos a la radioterapia convencional fraccionada de haz externo diaria en el mismo plazo. El objetivo de este enfoque es reducir la posibilidad de toxicidad tardía.

La radioterapia acelerada se refiere a la administración de fracciones múltiples por día mediante dosis diarias de radiación consistentes con las dosis de radioterapia convencional fraccionada de haz externo diaria. El objetivo es reducir el tiempo general de tratamiento; habitualmente es posible administrar dos o tres fracciones diarias con un intervalo de seis a ocho horas entre las fracciones.

El objetivo de la revisión fue:
Examinar la efectividad y la seguridad del aumento de la dosis de radiación de haz externo en los pacientes con diagnóstico reciente de GAG.

¿Cuáles son los principales hallazgos?
Se encontraron 11 ensayos (1537 participantes en los brazos relevantes para esta revisión) que cumplieron los criterios para la revisión. En general los pacientes con pronóstico deficiente no fueron elegibles para los ensayos aleatorios debido a su nivel de salud deficiente. Hubo un efecto beneficioso sobre la supervivencia general en los participantes con GAG que recibieron radioterapia convencional posoperatoria en comparación con los participantes que recibieron tratamiento médico de apoyo después de la cirugía. La radioterapia hipofraccionada tiene una eficacia similar en la supervivencia en comparación con la radioterapia convencional, en especial en los individuos de 60 años de edad y más con glioblastoma. No hubo diferencias claras en los efectos secundarios (efectos adversos) entre estos diferentes grupos de tratamiento. No hubo datos suficientes con respecto a otros resultados, a saber la supervivencia sin progresión y la calidad de vida entre estos diferentes grupos de tratamiento.

No hay datos suficientes con respecto a los resultados supervivencia, efectos adversos, supervivencia sin progresión y calidad de vida para el hiperfraccionamiento versus la radiación convencional fraccionada ni para la radiación acelerada versus la radiación convencional fraccionada.

Calidad de la evidencia:

La calidad de las pruebas varió de muy baja a alta. Algunos de los ensayos tuvieron un riesgo mayor de sesgo debido a la falta de detalles con respecto a cómo dividieron a los participantes en grupos de tratamiento, cuántos pacientes se perdieron durante el seguimiento y el posible informe selectivo de resultados como los efectos adversos.

Sólo cinco de los 11 ensayos incluidos se publicaron después del año 2000. La mayoría de los ensayos incluidos en el metanálisis se publicaron antes del año 2000 y actualmente están desactualizados. Estos ensayos más antiguos no distinguieron entre los diversos subtipos de GAG y utilizaron técnicas de radioterapia que no se utilizan actualmente como la radioterapia cerebral total en lugar de la radioterapia local (dirigida sólo al tumor y no a todo el cerebro).

¿Cuáles son las conclusiones?
La radioterapia convencional diaria posoperatoria mejora la supervivencia en los adultos con bienestar funcional y GAG en comparación con ninguna radioterapia posoperatoria.

La radioterapia hipofraccionada tiene una eficacia similar en la supervivencia en comparación con la radioterapia convencional, en especial en los individuos de 60 años de edad y más con glioblastoma.

Notas de traducción

La traducción y edición de las revisiones Cochrane han sido realizadas bajo la responsabilidad del Centro Cochrane Iberoamericano, gracias a la suscripción efectuada por el Ministerio de Sanidad, Servicios Sociales e Igualdad del Gobierno español. Si detecta algún problema con la traducción, por favor, contacte con Infoglobal Suport, cochrane@infoglobal-suport.com.

Резюме на простом языке

Увеличение дозы облучения при злокачественной глиоме

Актуальность:
Высокозлокачественная глиома (ГВСЗ - глиома высокой степени злокачественности) - это быстро растущая опухоль головного мозга в опорных клетках нервной системы, имеющая несколько подтипов, такие как глиобластома (астроцитома IV степени), анапластическая (III степень) астроцитома и анапластическая (III степень) олигодендроглиома. Она поражает примерно 5 человек из 100 000 в Европе и Северной Америке ежегодно. Ряд исследований выявил наилучшую стратегию облучения людей с ГВСЗ, в связи с чем необходимо рассмотреть эти исследования, чтобы понять, о чем они свидетельствуют. Ввиду токсичности все облучение не проводится в один день. Для достижения баланса между токсичностью и контролем над опухолью в течение нескольких дней облучение проводится в малых дозах.

Традиционная лучевая терапия подразумевает ежедневное облучение дозами от 180 до 200 сГр в день. Гипофракционированная лучевая терапия подразумевает более высокую суточную дозу (> 200 сГр в день), что, как правило, снижает общее число сеансов , а следовательно и продолжительность лечения в целом.

Гиперфракционированная лучевая терапия проводится с более низкой суточной дозой (<180 сГр в день), большим числом сеансов, а также несколькими сеансами в день для достижения общей дозы, как минимум равной таковой при традиционной дистанционной лучевой терапии за тот же промежуток времени. Целью этого подхода является снижение вероятности поздней токсичности.

Ускоренная лучевая терапия подразумевает несколько сеансов в день с ежедневными дозами облучения, сопоставимыми с таковыми при традиционной дистанционной лучевой терапии. Целью является сокращение общей длительности лечения; как правило, два или три сеанса в день могут проводиться с перерывом в шесть-восемь часов.

Цель обзора:
Рассмотреть эффективность и безопасность увеличения дозы облучения при дистанционной лучевой терапии у людей с впервые диагностированной ГВСЗ.

Каковы основные результаты?
Мы нашли 11 испытаний (1537 участников в соответствующих группах), отвечавших критериям нашего обзора. Люди с плохим прогнозом, как правило, не принимали участия в рандомизированных испытаниях в связи с состоянием здоровья. У участников с ГВСЗ, получавших традиционную послеоперационную лучевую терапию, отмечалось положительное влияние на выживаемость в сравнении с участниками, получавшими поддерживающий уход после операции. Гипофракционированная лучевая терапия имеет схожую эффективность в отношении выживаемости в сравнении с традиционной лучевой терапией, в частности у пациентов с глиобластомой в возрасте 60 лет и старше. Между группами вмешательств не было обнаружено каких-либо четких различий в отношении побочных эффектов. Данных касательно других исходов, а именно – выживаемости без прогрессирования и качества жизни, в группах вмешательств было недостаточно.

Данных касательно таких исходов, как выживаемость, нежелательные эффекты, выживаемость без прогрессирования и качество жизни, было недостаточно для сравнения гиперфракционированной и традиционной лучевой терапии, а также ускоренной и традиционной лучевой терапии.

Качество доказательств:

Качество доказательств варьировало от очень низкого до высокого. Некоторые испытания имели высокий риск смещения ввиду отсутствия подробной информации о распределении участников в группы вмешательств, потере (выбывания) пациентов в периоде наблюдения и вероятной избирательной отчетности о таких исходах, как неблагоприятные эффекты.

Лишь 5 из 11 включенных испытаний были опубликованы после 2000 года. Большинство испытаний, включенных в мета-анализ, были опубликованы до 2000 года и в настоящее время являются устаревшими. Эти старые испытания не проводили различия между подтипами ГВСЗ и использовали устаревшие методы лучевой терапии, такие как лучевая терапия всего мозга, а не местная терапия (направленная только на опухоль, а не на весь мозг).

Каковы выводы?
Традиционная ежедневная послеоперационная лучевая терапия повышает выживаемость взрослых с ГВСЗ в хорошем функциональном состоянии в сравнении с отсутствием послеоперационной лучевой терапии.

Гиперфракционированная лучевая терапия имеет схожую эффективность в отношении выживаемости в сравнении с традиционной лучевой терапией, в частности у пациентов с глиобластомой в возрасте 60 лет и старше.

Заметки по переводу

Перевод: Садикова Илюса Илфатовна. Редактирование: Кукушкин Михаил Евгеньевич. Координация проекта по переводу на русский язык: Cochrane Russia - Кокрейн Россия (филиал Северного Кокрейновского Центра на базе Казанского федерального университета). По вопросам, связанным с этим переводом, пожалуйста, обращайтесь к нам по адресу: cochrane.russia.kpfu@gmail.com; cochranerussia@kpfu.ru

Summary of findings(Explanation)

Summary of findings for the main comparison. Radiation versus no radiation for high grade glioma
  1. 1 The Anderson 1978 trial did not truly conceal the randomization process as allocation was based on dates of birth. Attrition was not completely described in all the trials. As such the quality of the evidence based on risk of bias was downgraded by 1.
    2 The trials used outdated radiotherapy techniques such as whole brain radiotherapy and did not use MRI to define the intracranial tumour extent. As such, the quality of the evidence based on indirectness was downgraded by 1.
    3 All trials showed a benefit with the use of postoperative radiation as compared to no radiation. The effect size was large with a HR 2.0 (1.58, 2.55) and a significant P value of P <0.00001. As such, the quality of evidence was upgraded by 1.

Radiation versus no radiation for high grade glioma
Patient or population: patients with high grade glioma
Settings: in the post-operative setting
Intervention: Radiation versus no radiation
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control Radiation versus no radiation
Overall survival Study population HR 2.01
(1.58 to 2.55)
397
(4 studies)
⊕⊕⊕⊝
moderate 1,2,3
 
1000 per 1000 1000 per 1000
(1000 to 1000)
High
1000 per 1000 1000 per 1000
(1000 to 1000)
Adverse effectsCould not be pooledCould not be pooledNot estimable289
(3 studies)
  
Progression free survivalCould not be pooledCould not be pooledNot estimable81
(1 study)
  
Quality of lifeCould not be pooledCould not be pooledNot estimable81
(1 study)
  
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; HR: Hazard ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 2 Hypofractionated radiation versus conventional radiation for high grade glioma

Summary of findings 2. Hypofractionated radiation versus conventional radiation for high grade glioma
  1. 1 Attrition was incompletely described in all the trials except for the Roa 2004 and Malmstrom 2012 trials. The Phillips 2003 had high risk of bias as the study was closed early due to poor accrual. The publication only included 68 participants. The authors did not comment on the planned sample size. As such, the quality of the evidence was downgraded by 2 for very serious risk of bias.
    2 Only 2 trials (Malmstrom 2012 and Roa 2004) examined glioblastoma individuals age 60 and over. The other older trials did not separate the results for grades 3 and 4 glioma nor was molecular subtype analysis available for the older outdated trials. As such, the quality of the evidence was downgraded by 1 (serious) for indirectness.

Hypofractionated radiation versus conventional radiation for high grade glioma
Patient or population: patients with high grade glioma
Settings:
Intervention: Hypofractionated radiation versus conventional radiation
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control Hypofractionated radiation versus conventional radiation
Overall survival Study population HR 0.95
(0.78 to 1.17)
943
(5 studies)
⊕⊝⊝⊝
very low 1,2
 
1000 per 1000 1000 per 1000
(1000 to 1000)
High
1000 per 1000 1000 per 1000
(1000 to 1000)
Adverse effectsCould not be pooledCould not be pooledNot estimable848
(4 studies)
  
Progression free survivalNot reportedNot reportedNot estimable0
(0)
  
Quality of lifeCould not be pooledCould not be pooledNot estimable361
(3 studies)
  
Overall survival for subgroup age 60 years and older glioblastoma Study population HR 1.16
(0.92 to 1.46)
293
(2 studies)
⊕⊕⊕⊕
high
 
1000 per 1000 1000 per 1000
(1000 to 1000)
High
1000 per 1000 1000 per 1000
(1000 to 1000)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; HR: Hazard ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Based on histopathological features, in 2007 World Health Organization (WHO) categorised gliomas from grade I (lowest grade) to grade IV (highest grade). High grade glioma is defined as WHO grades III and IV. The incidence of high grade glioma (HGG) is approximately 5 per 100,000 person-years in Europe and North America (Narayanan 2014). Gliomas account for almost 80% of primary brain tumours (Schwartzbaum 2006) and WHO grade IV glioblastoma is the most common type. Other types of malignant glioma are anaplastic astrocytoma, anaplastic oligodendroglioma and mixed anaplastic oligoastrocytoma (all WHO grade III).

The median overall survival for glioblastoma is just over one year (DeAngelis 2001; Stupp 2005). Numerous randomised studies have shown an overall survival benefit, favouring postoperative radiation compared to supportive care or single agent chemotherapy (Andersen 1978; Kristiansen 1981; Sandberg-Wollheim 1991). A Medical Research Council (MRC) study comparing radiation doses of 6000 centiGray (cGy) in 30 daily fractions to 4500 cGy in 20 daily fractions showed a small benefit favouring the higher dose (Bleehen 1991).

For most adult patients with HGG, specifically WHO grade IV, standard treatment involves maximal safe resection followed by radiation and chemotherapy (Stupp 2005). Although research has shown overall survival improving with temozolomide chemotherapy administered concurrently with radiation and postradiation for six months, the pattern of recurrence did not change (Oh 2011). The majority of recurrent HGG grows within 2 cm of the initially treated tumour target. With prolonged overall survival, there has been renewed interest in dose escalation as a way to improve local control, with the intent to further improve overall survival. However, radiation dose escalation is limited by radiation toxicity (Reddy 2013; Sminia 2012). The use of radiation to the brain has acute adverse effects such as fatigue, hair loss, increased intracranial pressure and possible late toxicity such as permanent radiation damage causing neurologic symptoms, known as radiation brain necrosis.

The optimal postoperative radiation dose and fractionation regimen has been the subject of research for decades, with several randomised controlled trials (RCTs) focusing on radiotherapy practice. With modernisation of radiotherapy delivery, there have been studies on hypofractionated (Bauman 1994), hyperfractionated (Shin 1983), and accelerated radiation regimens (Brada 1999; see Description of the intervention.)

The aim of hypofractionated radiation is to shorten overall treatment time, reducing the number of radiation treatment visits and hence radiation machine time and patient inconvenience. The aim of hyperfractionation is to potentially reduce late radiation toxicity by reducing the dose per fraction while still maintaining the intended tumour treatment dose. The aim of accelerated radiation is to reduce the overall treatment time by administering multiple radiation treatments per day. This regimen impedes the repopulation of rapidly growing tumour cells and theoretically improves tumour control. The focus of this Cochrane systematic review is to examine the benefits and harms of external beam radiation dose escalation for HGG.

We have excluded the topic of concurrent chemotherapy plus standard or dose escalated radiation versus radiation alone for HGG, as another Cochrane review has examined this topic (Stewart 2002). We have also excluded radiosurgery and brachytherapy boost trials, as the focus of this review was exclusively external beam radiotherapy.

Description of the condition

The 2007 WHO grading system has four categories (Louis 2007).

  • Grade I: slow-growing, non-malignant tumours associated with long-term overall survival.

  • Grade II: relatively slow-growing tumours that sometimes recur as higher grade tumours.

  • Grade III: malignant tumours that often recur as higher grade tumours.

  • Grade IV: rapidly growing, very aggressive malignant tumours.

This Cochrane review studied participants with WHO grade III and IV gliomas. Specific histologies for grade III glioma are: anaplastic astrocytoma, anaplastic oligodendroglioma and mixed anaplastic oligoastrocytoma. Grade IV gliomas are glioblastoma.

Description of the intervention

Initial treatment for adults with malignant glioma is surgical with the intent to perform a maximal safe resection. This allows pathologic confirmation of the radiographic diagnosis, improving local control and overall survival (Carapella 2011). In situations where resection is not safe, biopsy alone is considered to obtain pathology.

Following surgery, radiation and usually chemotherapy are standard treatments. For most people with glioblastoma, the approach is to treat with 6000 cGy of external beam radiation delivered in 200 cGy fractions per day (Monday to Friday excluding weekends) over 6 weeks with concurrent and adjuvant chemotherapy using temozolomide (Stupp 2005). However, for people with very poor prognosis HGG (e.g. older individuals with poor performance status and a diagnosis of glioblastoma), comfort measures without active intervention may be considered. Those over the age of 65 with glioblastoma may also be treated with chemotherapy alone or radiation using a shorter course (Arvold 2014; Malmstrom 2012; Roa 2004; Wick 2012).

Definitions of external beam radiation treatment regimens

Daily conventionally fractionated radiation therapy refers to the delivery of 180 cGy to 200 cGy per day.

Hypofractionated radiation therapy refers to the use of a higher daily dose of radiation (> 200 cGy per day) which typically reduces the overall number of fractions and therefore the overall treatment time.

Hyperfractionated radiation therapy refers to the use of a lower daily dose of radiation (< 180 cGy per day), a greater number of fractions and multiple fractions delivered per day in order to deliver a total dose at least equivalent to external beam daily conventionally fractionated radiation therapy in the same time frame. The aim with this approach is to reduce the potential for late toxicity.

Accelerated radiation therapy refers to the delivery of multiple fractions per day using daily doses of radiation consistent with external beam daily conventionally fractionated radiation therapy doses. The aim is to reduce the overall treatment time; typically, two or three fractions per day may be delivered with a six to eight hour gap between fractions.

This systematic review focuses on external beam radiation dose escalation trials in patients with HGG, and we have considered the following comparisons.

  • Daily conventionally fractionated radiation therapy versus no radiation therapy.

  • Hypofractionated radiation therapy versus daily conventionally fractionated radiation therapy.

  • Hyperfractionated radiation therapy versus daily conventionally fractionated radiation therapy.

  • Accelerated radiation therapy versus daily conventionally fractionated radiation therapy.

How the intervention might work

The aim of postoperative radiation is to treat residual tumour cells within the surgical bed and those known to infiltrate beyond the surgical site, which typically lie 1.5 cm beyond the tumour bed/residual disease. The therapeutic intent is to improve local control and overall survival.

Why it is important to do this review

There has been no published Cochrane review on this clinical question and no consensus as to optimal external beam radiation dose prescription. Furthermore, there are questions as to the appropriate radiation scheme specific to age, with some studies indicating an overall survival detriment with higher doses (Malmstrom 2012). There continues to be variability in practice (Ghose 2010), thus necessitating a high quality systematic review to guide practice.

The last two meta-analyses published did not appear in The Cochrane Library (Fine 1993; Laperriere 2002) and are now over a decade out of date. Therefore, a meta-analysis focused on radiation dose and delivery could provide evidence to support current practice and potentially guide future trials in the era of concurrent chemo-radiotherapy.

Objectives

To assess the effects of postoperative external beam radiation dose escalation in adults with HGG.

Methods

Criteria for considering studies for this review

Types of studies

Phase III randomised controlled trials (RCTs). Blinding was not possible due to the nature of radiation delivery and thus was not a criterion for eligibility.

Types of participants

  • Adults (18 years of age and older)

  • Pathological diagnosis of HGG (glioblastoma, anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic mixed oligoastrocytoma)

Types of interventions

All external beam radiotherapy regimens.

  • Daily conventionally fractionated radiation therapy versus no radiation therapy (supportive care alone).

  • Hypofractionated radiation therapy versus daily conventionally fractionated radiation therapy.

  • Hyperfractionated radiation therapy versus daily conventionally fractionated radiation therapy.

  • Accelerated radiation therapy versus daily conventionally fractionated radiation therapy.

Types of outcome measures

Primary outcomes
  • Overall survival (survival time in months from randomisation to death from any cause)

  • Adverse effects (a qualitative description of adverse effects was provided when adverse effects could not be pooled quantitatively)

Secondary outcomes
  • Progession-free survival in months from randomisation to disease progression or death

  • Quality of life using validated quality of life measurements (a qualitative description of quality of life was provided when quality of life could not be pooled quantitatively)

Search methods for identification of studies

Electronic searches

We searched the following electronic databases for studies.

  • Cochrane Central Register of Controlled Trials (CENTRAL, 2015, Issue 9) (Appendix 1).

  • MEDLINE (1977 to October 2015) (Appendix 2).

  • EMBASE (1980 to October 2015) (Appendix 3).

The search strategies were executed by the author in October 2015. We identified all relevant articles on PubMed and used the 'related articles' feature to perform further searches for newly published articles.

Searching other resources

Unpublished and grey literature

We searched the following databases for ongoing trials.

Handsearching

We handsearched the citation lists of included studies, key textbooks, and previous systematic reviews. We handsearched the reports of conferences in the following sources.

  • American Society for Therapeutic Radiation Oncology.

  • Canadian Association of Radiation Oncology.

  • European Society for Radiotherapy and Oncology.

  • Society of Neuro-Oncology.

  • The European Association of Neuro-Oncology (EANO).

  • British Society of Neuro-Oncology (BNOS).

Data collection and analysis

Selection of studies

We downloaded all titles and abstracts retrieved by electronic searching into EndNote and removed duplicates. Two review authors (LK, MT) examined the remaining references independently. We excluded studies that clearly did not meet the inclusion criteria, and we obtained copies of the full text of potentially relevant references. The two review authors (LK, MT) independently assessed the eligibility of retrieved studies. We resolved any disagreement by discussion between the two review authors, involving a third review author (AS) if necessary. We documented the reasons for exclusion.

Data extraction and management

For included studies, we extracted the following data.

  • Author, year of publication and journal citation.

  • Country.

  • Setting.

  • Inclusion and exclusion criteria.

  • Study design (RCTs).

  • Study population:

    • total number enrolled;

    • patient characteristics;

    • age (median and mean);

    • co-morbidities;

    • baseline performance status;

    • tumour grade;

    • surgical extent.

  • Intervention/comparator:

    • daily conventionally fractionated radiation therapy versus no radiation therapy;

    • hypofractionated radiation therapy versus daily conventionally fractionated radiation therapy;

    • hyperfractionated radiation therapy versus daily conventionally fractionated radiation therapy;

    • accelerated radiation therapy versus daily conventionally fractionated radiation therapy.

  • Risk of bias in study (Assessment of risk of bias in included studies).

  • Duration of follow-up.

  • Outcomes (for each outcome, we extracted the outcome definition and unit of measurement).

  • Results(we extracted the number of participants allocated to each intervention group, the total number analysed for each outcome and the missing participants).

We extracted results as follows.

  • For time-to-event data (survival), we extracted the log of the HR (log(HR)) and its standard error from trial reports. If studies did not report these, we attempted to estimate the log (HR) and its standard error using the methods of Parmar 1998.

  • For dichotomous outcomes (e.g. adverse events or deaths), if it was not possible to use HRs we extracted the number of participants in each treatment arm who experienced the outcome of interest and the number of participants assessed at endpoint, in order to estimate a risk ratio (RR).

  • If reported, we extracted both unadjusted and adjusted statistics.

  • Where possible, we extracted all data relevant to an intention-to-treat analysis, analysing participants in the groups to which they were assigned.

  • We noted the time points at which trials collected and reported outcomes.

Two authors (LK, MT) performed data extraction independently using a data abstraction form specially designed for the review. We resolved differences between authors by discussion, involving a third author (AS) if necessary.

Assessment of risk of bias in included studies

We assessed the risk of bias in included studies using the Cochrane tool for assessing risk of bias (Higgins 2011). Specifically, we evaluated the following domains (Appendix 4).

  1. Selection bias: random sequence generation and allocation concealment.

  2. Performance bias: blinding of participants and personnel was not possible due to the nature of radiation delivery.

  3. Detection bias: blinding of outcome assessment was not possible as the outcome assessors were not blinded to the intervention that the participant received.

  4. Attrition bias: incomplete outcome data.

  5. Reporting bias: selective reporting of outcomes.

  6. Other possible sources of bias.

Two authors (LK, MT) independently applied the 'Risk of bias' tool, resolving differences by discussion or by appeal to a third author (AS). We summarised results in both a 'Risk of bias' graph (Figure 1) and a 'Risk of bias' summary (Figure 2) (Higgins 2011). We interpreted results of our meta-analyses in light of the findings with respect to risk of bias.

Figure 1.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 2.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Measures of treatment effect

We used the following measures of treatment effect.

  • For time-to-event data, we used HR.

  • For dichotomous outcomes, we used RR.

  • For continuous outcomes, we used mean difference (MD) or standardized mean difference (SMD)

Unit of analysis issues

We did not include cluster-randomised trials or trials in which participants received more than one intervention. Furthermore, we did not consider multiple observations for the same outcome to be applicable.

Dealing with missing data

We did not impute missing outcome data for the primary outcome. If data were missing or if only imputed data were reported, we contacted trial authors to request data on the outcomes only in participants who were assessed.

Assessment of heterogeneity

We assessed heterogeneity between studies by visual inspection of forest plots and by estimating the percentage of heterogeneity between trials that could not be ascribed to sampling variation, using a formal statistical test of the significance of the heterogeneity (Deeks 2001; Higgins 2003). If there was evidence of substantial heterogeneity, we investigated and reported the possible reasons for this.

Assessment of reporting biases

We examined funnel plots corresponding to meta-analysis to assess the potential for small study effects such as publication bias, if we identified a sufficient number of studies (i.e. more than 10).

Data synthesis

For clinically similar studies, we pooled results in meta-analyses using the Cochrane statistical software, Review Manager (RevMan 2014). We used the random-effects model for analyses.

For time-to-event data, we pooled HRs using the generic inverse variance method in RevMan 2014.

Quality of evidence

We presented the overall quality of the evidence for each outcome according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, which takes into account issues not only related to internal validity (risk of bias, inconsistency, imprecision, publication bias) but also to external validity such as directness of results (Langendam 2013). We created a 'Summary of findings' table based on the methods described the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We used the GRADE checklist and GRADE Working Group quality of evidence definitions (Meader 2014).

  • High quality: Further research is very unlikely to change our confidence in the estimate of effect.

  • Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

  • Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

  • Very low quality: We are very uncertain about the estimate.

Subgroup analysis and investigation of heterogeneity

We performed a subgroup analysis of results, where possible for HGG participants 60 years of age and older, 65 years of age and older and 70 years of age and older.

Sensitivity analysis

We performed sensitivity analyses by excluding studies at high risk of bias.

Results

Description of studies

Results of the search

Our search yielded no records from CENTRAL, 743 records from MEDLINE and 1082 records from Embase. After de-duplication and abstract screening, we retained 69 possible studies for full-text screening and possible inclusion. We excluded studies that were not randomised trials and studies that did not involve the interventions of interest. This left a total of 11 included trials. Searches of online clinical trial registries identified no additional trials. Figure 3 shows the PRISMA flow diagram of study selection.

Figure 3.

Study flow diagram.

Included studies

We identified 11 studies for inclusion from full-text screening (Characteristics of included studies, Characteristics of excluded studies, Characteristics of studies awaiting classification)

  • Daily conventionally fractionated radiation therapy versus no radiation therapy (supportive care alone): four trials (397 participants in the meta-analysis).

  • Hypofractionated radiation therapy versus daily conventionally fractionated radiation therapy: five trials (944 participants in the meta-analysis).

  • Hyperfractionated radiation therapy versus daily conventionally fractionated radiation therapy: one trial (81 participants).

  • Accelerated radiation therapy versus daily conventionally fractionated radiation therapy: one trial (115 participants).

Daily conventionally fractionated radiation therapy versus no radiation therapy (supportive care alone)

Four RCTs assessed postoperative external beam radiotherapy versus no postoperative external beam radiotherapy (Andersen 1978; Kristiansen 1981; Walker 1978; Keime-Guibert 2007).

  • Andersen 1978 included 108 adults with glioblastoma. Participants born on even dates did not have postoperative radiotherapy, and those born on odd dates received postoperative radiation therapy. The postoperative radiation dose was 4500 cGy to whole brain, given in 4.5 to 5.0 weeks. Fifty-one participants were treated with radiation and 57 participants had no radiation and no chemotherapy.

  • Kristiansen 1981 was a prospective RCT that randomised 118 participants with grade III or IV astrocytoma to one of three arms:

    • Arm 1: 4500 cGy postoperative radiotherapy given daily in 180 cGy daily fractions to whole brain and bleomycin (excluded from the meta-analysis)

    • Arm 2: 4500 cGy postoperative radiotherapy given daily in 180 cGy daily fractions to whole brain and placebo (35 participants).

    • Arm 3: no postoperative radiation nor chemotherapy (38 participants).

  • In Walker 1978, 303 participants with grade III or IV were accrued from 1 September 1969 to 1 October 1972. The radiotherapy dose was 5000 to 6000 cGy given daily over 6 to 7 weeks to the whole brain. The trial had the following four arms:

    • Arm 1: supportive care alone (42 participants).

    • Arm 2: carmustine (BCNU) chemotherapy alone. (excluded from the meta-analysis)

    • Arm 3: radiotherapy alone (93 participants).

    • Arm 4: BCNU and radiotherapy. (excluded from the meta-analysis)

  • In Keime-Guibert 2007, 85 participants age 70 and over with newly diagnosed anaplastic astrocytoma or glioblastoma were randomized to:

    • Arm 1: supportive care alone (42 participants).

    • Arm 2: radiotherapy alone consisting of 5000 cGy given in daily fractions of 180 cGy (39 participants).

Hypofractionated radiation therapy versus daily conventionally fractionated radiation therapy

There were five included trials that randomised participants to hypofractionated radiation therapy versus conventionally fractionated radiation therapy (Bleehen 1991; Glinski 1993; Malmstrom 2012; Phillips 2003; Roa 2004):

  • Bleehen 1991 randomised 474 participants with malignant grade III or IV astrocytoma to 4500 cGy in 20 daily fractions (hypofractionated regimen) versus 6000 cGy in 30 daily fractions (conventional fractionation). The hypofractionated arm, 4500 cGy in 20 fractions, was given to a volume that encompassed all known and potential tumour. The conventional radiotherapy arm, 6000 cGy in 30 daily fractions, was given such that the initial 4000 cGy was given to a volume similar to the hypofractionated arm. Then a dose of 2000 cGy in 10 daily fractions was given to a reduced volume encompassing the visible tumour volume with a 1 cm margin. In the Bleehen 1991 trial, the majority (68%) of participants were between 18-59 years of age. Only 21% of participants were age 60 to 73 years of age.

  • Glinski 1993 was a prospective RCT consisting of 44 participants with glioblastoma and 64 participants with anaplastic astrocytoma. The hypofractionated arm consisted of 2000 cGy in five daily fractions to the whole brain. After a 4-week break, another 2000 cGy in 5 daily fractions was given to the whole brain followed by another 4-week break and a final 1000 cGy boost in five daily fractions to the gross visible tumour plus a 3 cm margin. The conventional fractionation arm was 5000 cGy in 25 daily fractions to the whole brain plus a 1000 cGy in five daily fraction boost to the gross tumour plus a 3 cm margin. The median age of participants was 43 years in the conventional arm and 46 years in the hypofractionated arm.

  • Phillips 2003 included 69 participants diagnosed with either anaplastic astrocytoma (in adults older than 45 years) or glioblastoma (adult, any age). These participants were randomised to hypofractionation (3500 cGy in 10 daily fractions) versus conventional fractionation (6000 cGy in 30 daily fractions). The treatment volume was the visible tumour and oedema with a 3 cm margin to the field edge. The median age in the conventional arm was 59 years and it was 58 years in the hypofractionated arm.

  • Malmstrom 2012 included 291 adults with glioblastoma over the age of 60, who were randomised to one of three arms. The trial used local radiotherapy (gross tumour volume plus a margin for suspected microscopic disease and day to day variation).

    • Arm 1: temozolomide chemotherapy alone (arm not included in the metaanalysis).

    • Arm 2: hypofractionated radiotherapy (3400 cGy in 10 daily fractions, 98 patients)

    • Arm 3: conventional fractionation (6000 cGy in 30 daily fractions, 100 patients)

  • Roa 2004 also included individuals at least 60 years of age with glioblastoma. Ninety-five participants were randomised to either hypofractionated radiotherapy (4000 cGy in 15 daily fractions) versus conventional radiotherapy (6000 cGy in 30 daily fractions). For participants randomised to the conventional radiotherapy arm, 4600 cGy in 23 daily fractions was prescribed to the planning target volume (PTV), defined as the preoperative enhancing tumour plus oedema with a 2.0 or 2.5 cm margin. Then 1400 cGy in seven daily fractions was given to the preoperative enhancing tumour (without oedema) plus a 2.5 cm margin.

Hyperfractionated radiation therapy versus daily conventionally fractionated radiation therapy

Shin 1985 compared hyperfractionated radiation therapy (with or without chemotherapy) versus conventionally fractionated radiation therapy (without chemotherapy). The trial was small with only 38 patients randomized to conventional fractionation (5800 cGy in 30 daily fractions), 43 patients to hyperfractionation (6141 cGy in 89 cGy fractions given three times a day every 2 to 4 hours for 4.5 weeks) and 43 patients to the same hyperfractionation with misonidazole.

Accelerated radiation therapy versus daily conventionally fractionated radiation therapy

There was only one trial which included an accelerated radiation therapy arm and a daily conventionally fractionated radiation therapy arm, without chemotherapy.

  • Prados 2001 randomised 231 adults with glioblastoma to one of four arms. The radiation volume where the dose was prescribed was defined as the contrast enhancing mass plus 3 cm:

    • Arm 1: accelerated fractionation, 7040 cGy in 44 fractions given twice a day (57 participants).

    • Arm 2: accelerated fractionation as above plus difluoromethylornithine (DFMO).

    • Arm 3: daily conventional fractionated radiation therapy, 5940 cGy in 180 cGy daily fractions (58 participants).

    • Arm 4: daily conventional fractionated radiation therapy plus DFMO.

As there were no other trials of accelerated radiation therapy versus daily conventional fractionated radiation therapy without chemotherapy, a meta-analysis was not possible.

Excluded studies

Radiotherapy versus no radiotherapy (supportive care alone)

We excluded the following studies:

  • Sandberg-Wollheim 1991 randomised participants who were all treated with procarbazine, CCNU and vincristine (PCV) chemotherapy. Half the participants received postoperative radiotherapy and the other half did not receive postoperative radiotherapy. Because there was no arm with supportive care alone, this trial was excluded.

  • Shapiro 1976 randomized participants who were all treated with chemotherapy (BCNU and vincristine). Half the the participants received postoperative radiotherapy and the other half did not receive postoperative radiotherapy. Because there was no arm with supportive care alone, this trial was excluded.

  • Walker 1980 randomized 467 participants to 1 of 4 groups: Arm 1 was semustine (MeCCNU) chemotherapy, Arm 2 was radiotherapy, Arm 3 was BCNU plus radiotherapy and Arm 4 was MeCCNU plus radiotherapy. Because there was no arm with supportive care alone, this trial was excluded.

  • Wick 2012 randomized participants 65 years of age and older to temozolomide chemotherapy alone versus radiotherapy alone. Because there was no arm with supportive care alone, this trial was excluded.

Hyperfractionated radiation therapy versus daily conventionally fractionated radiation therapy

We excluded the following studies.

  • Fulton 1984, as not all participants were randomised: 9 out of 42 were sequentially treated with hyperfractionation after the conventional radiotherapy arm was closed.

  • Deutch 1989 trial randomized participants to one of four groups:

    • Arm 1: conventional radiotherapy (6000 cGy in 30 to 35 daily fractions) plus BCNU.

    • Arm 2: conventional radiotherapy plus streptozotocin.

    • Arm 3: hyperfractionated radiotherapy (6600 cGy in 60 fractions given twice daily) plus BCNU.

    • Arm 4: conventional radiotherapy with metronidazole followed by BCNU.

As all arms had chemotherapy and not radiation alone, this trial was excluded.

  • Payne 1982 randomised 157 adults with grade III or IV astrocytoma to 5000 cGy in 25 daily fractions (conventional radiotherapy) versus 3600 to 4000 cGy in 36 to 40 fractions of 100 cGy fractions given every three hours. All participants received oral CCNU. Because there was no radiation alone arm, this trial was excluded.

  • Shin 1983 reported on a randomised controlled trial in 35 adults with grade III or IV astrocytoma treated with hyperfractionation and conventional radiation. Since both arms received chemotherapy (CCNU), this trial was excluded.

Accelerated radiation therapy versus daily conventionally fractionated radiation therapy

We excluded Simpson 1976 because there was no conventionally fractionated radiotherapy standard arm.

The Buckner 2006 trial examined conventional and accelerated radiation therapy with BCNU or with BCNU and cisplatin. As there were no radiotherapy alone arms, this trial was excluded.

The Marshall 2006 trial randomized patients to standard versus accelerated radiation therapy. However all the arms had chemotherapy. There was no radiation alone arm. As such, this trial was excluded. In addition, the authors did not report overall survival or progression-free survival outcomes.

Risk of bias in included studies

We assessed the risk of bias (Appendix 4; Characteristics of included studies; Figure 1; Figure 2) in included studies using the Cochrane tool for assessing risk of bias, evaluating the following domains (Higgins 2011).

Allocation

We assessed the method used to generate the allocation sequence as conferring a low risk of bias when investigators used any truly random process and when treatment allocation was protected before and until assignment. Andersen 1978 used a quasi-random process (odd or even date of birth to assign treatment arm), so we classified this study as being at high risk of bias for this category. Four trials did not describe the randomisation process in sufficient detail and thus we classified their risk of selection bias as unclear ( Kristiansen 1981; Phillips 2003; Shin 1985; Walker 1978). The rest of the trials had a low risk of selection bias.

Blinding

Blinding of participants and personnel is not possible due to the nature of radiation delivery. Blinding of outcome assessment was not done in the trials.

Blinding would not affect the outcome of overall survival and as such for this outcome, blinding was associated with low risk. However, lack of blinding may be associated with bias for the outcomes of adverse effects, progression free survival and quality of life. The extent to which lack of blinding may have biased the outcomes of adverse effects, progression free survival and quality of life was deemed to be unclear.

Incomplete outcome data

We defined low risk as less than 10% of participants not completing the outcome assessment. Not all of the studies described the percentage of missing data with sufficient detail to make a judgment (classified as unclear risk).

Selective reporting

Overall survival data were available for all included studies. Overall survival was deemed not to be subject to reporting bias. Other outcomes reported in the included trials such as progression-free survival, quality of life, and adverse effects may have been subject to possible selective outcomes reporting bias.

We examined funnel plots for the outcomes of overall survival (Figure 4; Figure 5). However, we did not run any tests for funnel plot asymemetry, as there were fewer than 10 studies in the meta-analyses. The test power was too low to distinguish chance from real asymmetry.

Figure 4.

Funnel plot of comparison: 1 Radiation versus no radiation, outcome: 1.1 Overall survival.

Figure 5.

Funnel plot of comparison: 2 Hypofractionated radiation versus conventional radiation, outcome: 2.1 Overall survival.

Other potential sources of bias

We included size of study as another possible source of bias. The definition of risk was defined as follows: low risk (200 or more participants in total), unclear risk (50 to 199 participants in total), high risk (fewer than 50 participants in total).

Effects of interventions

See: Summary of findings for the main comparison Radiation versus no radiation for high grade glioma; Summary of findings 2 Hypofractionated radiation versus conventional radiation for high grade glioma

Radiotherapy versus no radiotherapy (supportive care alone)

The meta-analysis for this comparison included four randomised controlled trials (RCTs) in adults with HGG comparing conventional postoperative radiotherapy versus no postoperative radiation (Andersen 1978; Kristiansen 1981; Walker 1978; Keime-Guibert 2007).

Overall survival

Overall, there was benefit for postoperative radiotherapy compared to no radiotherapy (HR 2.01, 95% confidence interval (CI) 1.58 to 2.55, P < 0.00001; Analysis 1.1). The included trials were moderate in quality based on the GRADE methodology (Summary of findings for the main comparison; Appendix 5).

The analysis for heterogeneity for the trials examining overall survival between postoperative radiotherapy versus no radiotherapy revealed the following characteristics: I2 = 0%, P = 0.51. This suggests that heterogeneity may not be important.

For the sensitivity analysis, we rated Andersen 1978 as being at high risk of bias and excluded them from the analysis (Analysis 1.2). This resulted in continued benefit for postoperative radiotherapy compared to no radiotherapy (HR 2.20, 95% CI 1.67 to 2.90, P < 0.00001).

The subgroup analysis (based on age 60 and over, 65 and over and 70 and over) was not possible.

Adverse effects

The Andersen 1978 trial did not describe adverse events.

The Keime-Guibert 2007 trial reported that all patients in the radiotherapy group tolerated the treatment. One patient had transient somnolence shortly after the completion of radiation.

The Kristiansen 1981 trial reported no serious complications during the trial. Irradiation and bleomycin were well tolerated.

Walker 1978 described haematologic toxicity with BCNU. In general, the authors reported that therapy was well tolerated; they did not encounter any serious complications secondary to haematologic changes, and they did not note any significant toxicity attributable to radiation.

Progression free survival

None of the trials reported on progression free survival except the Keime-Guibert 2007 trial. As such progression free survival could not be pooled. The Keime-Guibert 2007 trial reported that the median progression free survival was 14.9 weeks with radiotherapy versus 5.4 weeks with supportive care alone, P <0.001.

Quality of life

None of the trials reported on quality of life outcomes except the Keime-Guibert 2007 trial. As such quality of life outcomes could not be pooled. Global assessments in health-related quality of life in the Keime-Guibert 2007 trial did not differ significantly between the two groups.

Hypofractionated radiation therapy versus daily conventionally fractionated radiation therapy

Five trials randomised adults with HGG to hypofractionated radiation versus conventional radiation (Bleehen 1991; Glinski 1993; Malmstrom 2012; Phillips 2003; Roa 2004).

Overall survival

The hazard ratio for overall survival between hypofractionated radiation versus conventional radiation was 0.95 (95% CI 0.78 to 1.17, P = 0.63; Analysis 2.1). The included trials were very low quality based on GRADE assessment (Summary of findings 2; Appendix 6).

The analysis for heterogeneity for the trials examining overall survival for postoperative hypofractionated radiotherapy versus conventional radiotherapy revealed the following characteristics: I2 = 43%, P = 0.13. This suggests that there may be moderate heterogeneity.

For the subgroup analysis based on age, glioblastoma participants over the age of 60 years (Malmstrom 2012; Roa 2004) were pooled, the HR for overall survival was 1.16 (95% CI 0.92, 1.46, P = 0.21). The included trials were high based on GRADE assessment (Summary of findings 2; Appendix 7). The analysis for heterogeneity for the trials examining overall survival for postoperative hypofractionated radiotherapy versus conventional radiotherapy (for the subgroup of glioblastoma participants age 60 year and older) revealed the following characteristics: I2 = 0%, P = 0.86. This suggests that heterogeneity may not be important.

No other subgroup analysis based on age (age 65 and over, age 70 and over) could be pooled.

Adverse effects

Bleehen 1991 reported that 83% of participants treated to 4500 cGy compared to 81% treated to 6000 cGy reported no adverse events from the radiotherapy. There were no major differences in acute adverse effects between the two radiotherapy arms.

Glinski 1993 reported that radiotherapy was well tolerated in the hypofractionated and conventionally fractionated groups. All participants had total alopecia and mild erythema of the scalp. Investigators reported skin reactions in the hypofractionated group to be no more severe than those in the conventionally fractionated group. One participant in the hypofractionated group developed symptomatic radiation necrosis requiring surgery.

The Malmstrom 2012 trial reported that the most common grade 3 to 4 adverse events in the temozolomide alone group were neutropenia (12 out of 119 participants) and thrombocytopaenia (18 out of 119 participants). Two participants had fatal infections (1 out of 119 participants in the temozolomide group and 1 out of 100 in the conventional radiotherapy group). Another participant in the temozolomide group had grade 2 thrombocytopaenia and died after complications from surgery for gastrointestinal bleeding.

Acute toxicity was reported as mild and equally distributed between the two arms in the Phillips 2003 trial. Investigators reported did not report late toxicity.

Roa 2004 did not describe adverse effects.

Progression free survival

None of the trials reported on progression-free survival.

Quality of life

Because of the low number of participants who completed the European Organisation for Research and Treatment of Cancer quality of life questionnaires (EORTC QLQ 30), Malmstrom 2012 suggested caution in the interpretation of this outcome. Nevertheless, patients in the temozolomide chemotherapy alone group reported better quality of life compared to patients in the radiotherapy groups.

The Roa 2004 trial used the Functional Asssessment of Cancer Therapy- Brain (FACT- Br) quality of life questionnaire. However, number of completed quality of life questionnaires was too low to make meaningful comparisons between standard and abbreviated radiotherapy.

The Phillips 2003 trial also reported that the number of completed quality of life questionnaires was too low for any formal comparisons.

No other included hypofractionated trials reported on quality of life outcomes.

Hyperfractionated radiation therapy versus daily conventionally fractionated radiation therapy

One trial compared hyperfractionated radiation therapy versus daily conventionally fractionated radiation therapy (Shin 1985).

Overall survival

The Shin 1985 trial reported that the 1 year actuarial survival was 20% for conventional fractionation versus 41% for hyperfractionation, P = 0.007. This trial did not provide subgroup analyses by age.

Adverse effects

Shin 1985 described more skin reactions (erythema, dry and moist desquamation) in the hyperfractionated group compared to the conventionally fractionated group.

Progression free survival

Progression-free survival was not reported (Shin 1985).

Quality of life

Quality of life was not reported (Shin 1985).

Accelerated radiation therapy versus daily conventionally fractionated radiation therapy

There was only one trial (Prados 2001) which included an accelerated radiation therapy arm and a daily conventionally fractionated radiation therapy arm, without chemotherapy.

Overall survival

As there were no other trials of accelerated radiation therapy versus daily conventional fractionated radiation therapy without chemotherapy, a meta-analysis was not possible.

The Prados 2001 trial reported a median overall survival of 40 weeks for the accelerated arm and 37 weeks for the conventionally fractionated radiation therapy, P = 0.48.

Subgroup analysis by age was not reported for the Prados 2001 trial.

Adverse effects

The Prados 2001 trial reported that the treatment arms containing DFMO resulted in more toxicity (namely myelosuppression) than those receiving radiotherapy alone. Based on the National Cancer Institute (NCI) Common Toxicity Criteria, grade 3 or 4 myelosuppression occurred in two participants (out of 57) treated with accelerated radiation and DFMO, one participant (out of 59) treated with conventional radiation and DFMO and one participant (out of 57) treated with accelerated radiation alone. None of the 58 participants treated with conventional radiotherapy developed grade 3 or 4 myelosuppression. Grades 3 and 4 gastrointestinal toxicity was also more common in the DFMO arms (one individual in the accelerated radiotherapy and DFMO arm and three in the conventional radiotherapy and DFMO arm), versus the arms without DFMO (no individuals). Skin reactions during radiation were mild and were equally balanced among all four arms. Grade 3 ototoxicity (three participants) was noted only in the DFMO arms. Authors reported no cases of cerebral necrosis from radiation.

Progression-free survival

As there were no other trials of accelerated radiation therapy versus daily conventional fractionated radiation therapy without chemotherapy, a meta-analysis for progression-free survival was not possible. The only included trial, Prados 2001 reported 19 weeks progression-free survival for the accelerated arm versus 16 weeks for the conventionally fractionated radiation therapy arm, P = 0.32.

Quality of life

The only included trial did not report on quality of life outcomes (Prados 2001).

Discussion

Summary of main results

Postoperative conventional daily radiotherapy improves survival for adults with good functional well-being and HGG compared to no postoperative radiotherapy (supportive care alone).

Hypofractionated radiation therapy has similar efficacy for survival as compared to conventional radiotherapy, particularly for individuals aged 60 and older with glioblastoma.

There is insufficient data regarding hyperfractionation versus conventionally fractionated radiation (without chemotherapy) and insufficient data regarding accelerated radiation versus conventionally fractionated radiation (without chemotherapy).

There are HGG subsets who have poor prognosis even with treatment (e.g. glioblastoma histology, older age and poor performance status). These poor prognosis HGG individuals have generally been excluded from the randomised trials based on poor performance status. No randomised trial has compared comfort measures or best supportive care with an active intervention using radiotherapy or chemotherapy in these poor prognosis patients.

Overall completeness and applicability of evidence

Radiotherapy versus no radiotherapy (supportive care alone)

Overall, there was a survival benefit for postoperative conventionally fractionated radiotherapy compared to no radiotherapy (HR 2.01, 95% confidence interval (CI) 1.58 to 2.55, P < 0.00001; Analysis 1.1), moderate GRADE quality evidence (Summary of findings for the main comparison).

The trials generally included only incomplete descriptions of radiation toxicity. Some of the trials reported no significant toxicity attributable to radiation (Keime-Guibert 2007; Kristiansen 1981; Walker 1978).

It is important to note that all the included trials (except for Keime-Guibert 2007) are many decades old (publication dates range from 1978 to 1981). Since then, there have been many advances.

  • Improved pathological diagnosis (histological and molecular), to distinguish between glioblastoma and high grade oligodendroglioma.

  • Improved clinical (e.g. age, performance status) and pathological prognostic factor determination (e.g. MGMT methylation, 1p, 19 q LOH, and mutated isocitrate dehydrogenase also known as mIDH1 status)

  • Use of imaging for radiation planning (transition from planning based on computed tomography (CT) to magnetic resonance imaging (MRI))

  • Advances in radiation planning techniques (progression from two dimensional radiation planning to three dimensional radiation planning, transition from whole brain radiotherapy to local radiotherapy)

Most postradiotherapy recurrence (more than 90% of cases) occurs at the original site (Hochberg 1980; Wallner 1989). Based on the recurrence pattern and better tumour localisation using MRI, local radiotherapy targeted to the visible tumour plus a margin in the order of 2 cm is currently used rather than whole brain radiotherapy. The use of whole brain radiotherapy in HGG unnecessarily exposes normal brain tissue to radiation toxicity without improving tumour control nor overall survival.

In addition, these older trials included adults with grade III and grade IV glioma, whereas there is now a consensus that trials should no longer lump these grades of HGG together, as the clinical behaviour and prognosis of grade III and IV glioma are very different. Specialists can now perform molecular diagnoses for subtypes of glioma, such as 1p, 19q LOH for oligodendroglioma, which are helpful for differentiating grade III oligodendroglioma from high grade astrocytoma. The median survival for treated grade III anaplastic oligodendroglioma with 1p 19q LOH is in the range of 15 years (Cairncross 2013; Van den Bent 2013). Adults with glioblastoma, however, have much shorter overall survival. A modern population-based study in adults diagnosed with primary malignant brain tumours in Europe from 2000 to 2007 reported that five-year overall survival for glioblastoma was only 6% (Visser 2015). Even within glioblastoma, MGMT methylation and mIDH1 status further refine prognosis and is predictive of treatment outcomes (Macaulay 2015).

Applicabilty of evidence:

It is also important to note that while postoperative conventionally fractionated radiotherapy for malignant glioma is generally associated with improved overall survival compared to no postoperative radiotherapy, the included trials could not provide information as to whether certain subsets of people (e.g. poor performance status, multiple lobe involvement, older age) have a significant overall survival advantage with the use of postoperative radiotherapy. In this group, comfort measures or supportive care alone may be the best option.

Wick 2012 included participants with anaplastic astrocytoma or glioblastoma, aged 65 and over. In this trial, temozolomide alone was no different from radiotherapy alone in terms of overall survival. Median event-free survival was longer in those with O6 -methylguanine-DNA methyltransferase (MGMT) promoter methylation who received temozolomide versus radiotherapy (8.4 months, 95% CI 5.5 to 11.7 versus 4.6 months, 95% CI 4.2 to 5.0, P < 0.0001).

The trial by Wick 2012 indicates that in individuals aged 65 and over with anaplastic astrocytoma or glioblastoma, the option of postoperative temozolomide chemotherapy is not inferior to postoperative radiotherapy. In this group, those with methylated MGMT have longer event-free survival when treated with temozolomide chemotherapy compared to radiotherapy alone.

Hypofractionated radiation therapy versus daily conventionally fractionated radiation therapy

Overall, hypofractionated radiation therapy has similar efficacy for survival as compared to conventional radiotherapy.The hazard ratio for overall survival between hypofractionated radiation versus conventional radiation was 0.95 (95% CI 0.78 to 1.17, P = 0.63; Analysis 2.1), very low GRADE quality evidence (Summary of findings 2).

Radiation toxicities in the Bleehen 1991 and Glinski 1993 trials were similar between hypofractionated and conventional radiotherapy.

Subgroup analysis for glioblastoma 60 years of age and older:

The benefit of hypofractionated radiation therapy is reduced overall treatment time, which is less burdensome, particularly in older frail individuals, compared to a protracted radiotherapy course. In the subgroup analysis for the two trials which included glioblastoma participants all age 60 and over, survival was similar with hypofractionated radiation as compared to conventionally fractionated radiation HR 1.16 (95% CI 0.92 to 1.46, P = 0.21; Analysis 2.2), high GRADE quality evidence (Summary of findings 2).

In Malmstrom 2012, all participants had glioblastoma and were aged 60 years or older. Median overall survival was longer with temozolomide compared to conventional radiotherapy (8.3 months, 95% CI 7.1 to 9.5, versus 6.0 months, 95% CI 5.1 to 6.8; HR 0.70, 95% CI 0.52 to 0.93, P = 0.01), but not compared to hypofractionated radiotherapy (7.5 months, 95% CI 6.5 to 8.6; HR 0.85, 95% CI 0.64 to 1.12, P = 0.24).

In particular for the subset of people with glioblastoma (age 70 and over), Malmstrom 2012 reported that overall survival was worse for conventional radiotherapy (6000 cGy in 30 daily fractions) than either hypofractionated radiotherapy (3400 cGy in 10 daily fractions) or temozolomide chemotherapy. The HR for temozolomide versus conventional radiotherapy was 0.35 (95% CI 0.21 to 0.56, P <0.0001), favouring temozolomide. The HR for hypofractionated radiotherapy versus conventional radiotherapy was 0.59 (95% CI 0.37 to 0.93, P = 0.02), favouring hypofractionated radiotherapy.

In terms of overall adverse events in Malmstrom 2012, there were more infections/fever in the conventional radiotherapy arm (14%) than in the hypofractionated arm (7%). In addition, there were more intracranial haemorrhages in the conventional arm (3%) versus the hypofractionated arm (0%). Seizures occured in 13% of participants in the conventional arm versus 7% in the hypofractionated arm. Haematologic adverse effects were more common in those treated with temozolomide (grades 2 to 4 neutropenia, pancytopenia, thrombocytopaenia ranged from 2% to 21%) compared to none of the patients treated with radiotherapy. Nausea and vomiting were also more common in those treated with temozolomide (incidence of grades 2 and 3 nausea and vomiting ranged from 3% to 7%) than in those treated with radiotherapy (1% to 5%).

The Roa 2004 trial reported no difference in overall survival for individuals 60 years of age and older with glioblastoma treated with hypofractionated radiotherapy (4000 cGy in 15 daily fractions) compared to conventional radiotherapy (6000 cGy in 30 daily fractions). Overall survival was 5.6 months for hypofractionated radiotherapy compared to 5.1 months for conventional radiotherapy (P = 0.57).

Applicabilty of the evidence:

The included trials in this meta-analysis do not provide sufficient data to determine the optimal dose fractionation schemes for anaplastic glioma (astrocytoma, oligodendroglioma) as the included trials have combined results for anaplastic glioma and glioblastoma. There are however, trials which have focused solely on glioblastoma management.

Glioblastoma up to the age of 70

The Stupp 2005 trial and 5-year follow-up data Stupp 2009 has defined the standard of care for glioblastoma adults, up to age 70 with WHO performance status 0 to 2, who have no contraindication to radiotherapy or temozolomide chemotherapy. Adults treated with postoperative conventionally fractionated radiotherapy (6000 cGy in 30 daily fractions) had better overall survival with the addition of concurrent and adjuvant temozolomide chemotherapy versus the same postoperative radiotherapy alone. Overall survival in this trial was 27.2% (95% CI 22.2 to 32.5) at 2 years versus 10.9% (95% CI 7.6 to 14.8), P < 0.0001 for radiotherapy and temozolomide versus radiotherapy alone, respectively. Whether similar outcomes could be achieved with hypofractionated radiotherapy and temozolomide chemotherapy is not known in this group of people.

Conventionally fractionated radiation therapy (6000 cGy in 30 daily fractions) with concurrent and adjuvant temozolomide chemotherapy is the standard of care for adults with glioblastoma eligible for treatment.

Glioblastoma 60 years of age and older

For the pooled subgroup analysis of individuals 60 years of age and older with glioblastoma in the Malmstrom 2012; Roa 2004 trials, hypofractionated radiation therapy is associated with similar survival as compared to conventionally fractionated radiation.

The phase III randomized trial of hypofractionated radiotherapy (4000 cGy in 15 daily fractions) alone versus the same radiotherapy and temozolomide chemotherapy (NCT00482677) in glioblastoma individuals 65 years of age and older has been reported in abstract form (Perry 2016). The addition of temozolomide chemotherapy to hypofractionated radiation was associated with improved survival as compared to hypofractionated radiation alone, HR 0.67 (95% CI 0.56 to 0.80, P <0.0001) and improved progression-free survival, HR 0.50 (95% CI 0.41 to 0.60, P <0.0001).

Glioblastoma 70 years of age and older

For people aged 70 and over with glioblastoma and methylated MGMT, temozolomide alone (without postoperative radiotherapy) is an option.

Hyperfractionated radiation therapy versus daily conventionally fractionated radiation therapy

There is insufficient data regarding hyperfractionation versus conventionally fractionated radiation (without chemotherapy).

The use of hyperfractionated radiation therapy is inconvenient, requires significant radiation machine time and has been associated with more severe acute skin reactions compared to conventional radiation (Shin 1985).

Accelerated radiation therapy versus daily conventionally fractionated radiation therapy

There is insufficient data regarding accelerated radiation versus conventionally fractionated radiation (without chemotherapy).

The use of accelerated radiation therapy is inconvenient and requires significant radiation machine time. Toxicity attributable to radiation was similar between the accelerated and conventional radiation arms in the Prados 2001 trial.

Prados 2001 defined progression as an increase in the size of the contrast enhancing tumour based on MRI of at least 25% using the product of the two longest perpendicular diameters or the development of new lesions.

Current practice favours MRI for assessment of progression rather than CT due to greater sensitivity to small lesions and better visualisation of the posterior fossa compared to CT. However, there has been increasing recognition that enlargement of contrast enhancement after treatment for high grade glioma may be the result of treatment effect rather than true tumour growth (Huang 2015). Within three months from the end of radiation treatment, 20% to 30% of adults show increased contrast enhancing tumour size that settles with time without changes in treatment, known as pseudoprogression. Failure to recognise pseudoprogression is prone to artificially shorten the progression-free survival interval.

To address this issue and others, in 2010 the Response Assessment in Neuro-Oncology (RANO) Working Group proposed updated response criteria for high grade glioma (Wen 2010). The revised criteria not only includes radiographic findings but also incorporates steroid use and clinical status. Furthermore, the 2010 RANO criteria excludes adults with enlarging contrast enhancement during the first 12 weeks after radiation from entry into new clinical trials unless the progression is largely outside the radiation field.

The Prados 2001 trial predates the 2010 RANO criteria. As such, progression-free survival data from Prados 2001 may not be an accurate reflection of true tumour progression.

Quality of the evidence

Based on the GRADE criteria (Appendix 5; Appendix 6; Appendix 7), the quality of the evidence ranges from very low to high quality (Summary of findings for the main comparison; Summary of findings 2). We classified some trials as being at a higher risk of bias when they did not clearly describe the method of randomisation or details relating to attrition. Only 5 out of 11 trials were published after the year 2000; most are therefore now out of date. These older trials did not distinguish the various subtypes of HGG such as glioblastoma and anaplastic oligodendroglioma and used outdated radiotherapy techniques such as whole brain radiotherapy rather than local radiotherapy.

Potential biases in the review process

This meta-analysis is biased toward older outdated trials. The older trials are severely flawed because at the time of investigation, the importance of pathologically separating glioblastoma from anaplastic astrocytoma or anaplastic oligodendroglioma was still unknown. Radiation planning techniques in the older trials were also outdated (lack of MRI based planning and lack of local radiotherapy volumes). Furthermore, outcomes stratified by known prognostic factors, both clinical and molecular are missing from many of the older trials.

Agreements and disagreements with other studies or reviews

This meta-analysis agrees with the older meta-analyses (Fine 1993; Laperriere 2002). However, this present meta-analysis differs from the older meta-analyses as radiotherapy arms without chemotherapy were considered. Furthermore, the present meta-analysis includes more recent trials and it includes further information regarding the use of hypofractionation in glioblastoma individuals over the age of 60.

Authors' conclusions

Implications for practice

There is moderate quality of evidence that postoperative conventional daily radiotherapy improves survival for adults with good performance status and HGG compared to no postoperative radiotherapy (supportive care alone). Our certainty in the effect is at risk of bias due to the lack of applicability from the age of the studies and heterogeneous participants recruited.

There is very low quality of evidence that hypofractionated radiation therapy has similar efficacy for survival as compared to conventional radiotherapy, also due to the risk of bias and lack of applicability arising from the age of the studies and heterogenous participants recruited. However there is high quality of evidence that hypofractionated radiation therapy has similar efficacy for survival, particularly for the subgroup of individuals aged 60 and older with glioblastoma.

There are HGG subsets who have poor prognosis even with treatment (e.g. older glioblastoma patients with poor performance status). Randomised trials have generally excluded these poor prognosis patients from randomised trials on this basis.

There is insufficient evidence regarding the benefits (overall survival, progression-free survival, quality of life) and risks associated with hyperfractionated radiation or accelerated radiation as compared to conventional radiation (without chemotherapy).

Implications for research

Classification of gliomas based on molecular characteristics will help identify more homogeneous groups of people for trial entry. Further research is necessary to explore the use of novel chemotherapy or molecular targeted agents with various radiation regimens. Not only are the outcomes of overall survival and complete reporting of toxicity important, but future trials should also report on validated quality of life outcomes.

Acknowledgements

We thank Robin Grant for clinical and editorial advice, Gail Quinn, Clare Jess and Tracey Harrison for their contribution to the editorial process. Jane Hayes and Jo Platt for designing and running the original searches.

This project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to the Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.

The review is funded in part by a grant from the European Association of Neuro-Oncology.

We would like to thank all our the external peer reviewers, including Helen Bulbeck.

Data and analyses

Download statistical data

Comparison 1. Radiation versus no radiation
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Overall survival4 Hazard Ratio (Random, 95% CI)2.01 [1.58, 2.55]
2 Overall survival (sensitivity analysis)3 Hazard Ratio (Random, 95% CI)2.20 [1.67, 2.90]
Analysis 1.1.

Comparison 1 Radiation versus no radiation, Outcome 1 Overall survival.

Analysis 1.2.

Comparison 1 Radiation versus no radiation, Outcome 2 Overall survival (sensitivity analysis).

Comparison 2. Hypofractionated radiation versus conventional radiation
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Overall survival5 Hazard Ratio (Random, 95% CI)0.95 [0.78, 1.17]
2 Overall survival (age 60 years and older glioblastoma)2 Hazard Ratio (Random, 95% CI)1.16 [0.92, 1.46]
Analysis 2.1.

Comparison 2 Hypofractionated radiation versus conventional radiation, Outcome 1 Overall survival.

Analysis 2.2.

Comparison 2 Hypofractionated radiation versus conventional radiation, Outcome 2 Overall survival (age 60 years and older glioblastoma).

Appendices

Appendix 1. CENTRAL Search Strategy

#1 MeSH descriptor: [Glioma] explode all trees
#2 (glioma* or glioblastoma* or astrocytoma* or oligodendroglioma* or oligoastrocytoma*)
#3 #1 or #2
#4 MeSH descriptor: [Radiotherapy] explode all trees
#5 Any MeSH descriptor with qualifier(s): [Radiotherapy - RT]
#6 (radiotherap* or radiation or irradiation)
#7 #4 or #5 or #6
#8 (fraction* or hyperfractionat* or hypofractionat* or accelerat* or dose or dosage)
#9 MeSH descriptor: [Dose Fractionation] this term only
#10 #8 or #9
#11 #7 and #10
#12 MeSH descriptor: [Brachytherapy] explode all trees
#13 MeSH descriptor: [Radiosurgery] explode all trees
#14 brachytherapy or radiosurgery
#15 #11 or #12 or #13 or #14
#16 #3 and #15

Appendix 2. MEDLINE (Ovid) search strategy

1 exp Glioma/
2 (glioma* or glioblastoma* or astrocytoma* or oligodendroglioma* or oligoastrocytoma*).mp.
3 1 or 2
4 exp Radiotherapy/
5 radiotherapy.fs.
6 (radiotherap* or radiation or irradiation).mp.
7 4 or 5 or 6
8 (fraction* or hyperfractionat* or hypofractionat* or accelerat* or dose or dosage).mp.
9 dose fractionation/
10 8 or 9
11 7 and 10
12 brachytherapy.mp. or Brachytherapy/
13 radiosurgery.mp. or Radiosurgery/
14 11 or 12 or 13
15 3 and 14
16 randomized controlled trial.pt.
17 controlled clinical trial.pt.
18 randomized.ab.
19 placebo.ab.
20 clinical trials as topic.sh.
21 randomly.ab.
22 trial.ti.
23 16 or 17 or 18 or 19 or 20 or 21 or 22
24 15 and 23

key:
mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, pt=publication type, fs=floating subheading, ab=abstract, ti=title, sh=subject heading

Appendix 3. Embase (Ovid) search strategy

1 exp glioma/
2 (glioma* or glioblastoma* or astrocytoma* or oligodendroglioma* or oligoastrocytoma*).mp.
3 1 or 2
4 exp radiotherapy/
5 rt.fs.
6 (radiotherap* or radiation or irradiation).mp.
7 4 or 5 or 6
8 (fraction* or hyperfractionat* or hypofractionat* or accelerat* or dose or dosage).mp.
9 radiation dose fractionation/
10 8 or 9
11 7 and 10
12 bracytherapy.mp. or exp brachytherapy/
13 radiosurgery.mp. or exp radiosurgery/
14 11 or 12 or 13
15 3 and 14
16 crossover procedure/
17 double-blind procedure/
18 randomized controlled trial/
19 single-blind procedure/
20 random*.mp.
21 factorial*.mp.
22 (crossover* or cross over* or cross-over*).mp.
23 placebo*.mp.
24 (double* adj blind*).mp.
25 (singl* adj blind*).mp.
26 assign*.mp.
27 allocat*.mp.
28 volunteer*.mp.
29 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28
30 15 and 29

key:
[mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]

Appendix 4. Assessment of risk of bias

Random sequence generation

  • Low risk of bias e.g. participants assigned to treatments on basis of a computer-generated random sequence or a table of random numbers

  • High risk of bias e.g. participants assigned to treatments on basis of date of birth, clinic identification number or surname, or no attempt to randomise participants

  • Unclear risk of bias e.g. not reported, information not available

Allocation concealment

  • Low risk of bias e.g. where the allocation sequence could not be foretold

  • High risk of bias e.g. allocation sequence could be foretold by patients, investigators or treatment providers

  • Unclear risk of bias e.g. not reported

Attrition

We recorded the proportion of participants whose outcomes were not reported at the end of the study. We coded a satisfactory level of loss to follow-up for each outcome as:

  • low risk of bias, if fewer than 20% of patients were lost to follow-up and reasons for loss to follow-up were similar in both treatment arms;

  • high risk of bias, if more than 20% of patients were lost to follow-up or reasons for loss to follow-up differed between treatment arms;

  • unclear risk of bias if loss to follow-up was not reported.

Selection reporting of outcomes

  • Low risk of bias e.g. review reports all outcomes specified in the protocol

  • High risk of bias e.g. It is suspected that outcomes have been selectively reported

  • Unclear risk of bias e.g. It is unclear whether outcomes had been selectively reported

Appendix 5. GRADE checklist (radiotherapy versus no radiotherapy 4 trials)

Risk of bias

  1. Was random sequence generation used (ie. no potential for selection bias)?Andersen 1978 had a high risk of bias as randomisation was dependent on even or odd dates of birth.

  2. Was allocation concealment used (i.e. no potential for selection bias)? Not applicable.

  3. Was there blinding of participants and personnel (i.e. no potential for performance bias)? Not applicable.

  4. Was there blinding of outcome assessment (i.e. no potential for detection bias)? Not applicable.

  5. Was an objective outcome used? Yes, overall survival is objective and is the primary outcome. Adverse effects, progression free survival and quality of life are subject to reporting bias.

  6. Were more than 80% of participants enrolled in trials included in the analysis (ie. no potential attrition bias)? Attrition was not completely described in all the trials.

  7. No other biases reported (no potential of other bias)? No

  8. Did the trials end as scheduled (i.e. not stopped early)? Yes, all trials ended as scheduled.

Overall risk of bias was downgraded as serious (-1).

Inconsistency

  1. Point estimates did not vary widely (i.e. no clinical meaningful inconsistency)? The point estimates for survival did not vary widely.

  2. To what extent do confidence intervals overlap? The confidence intervals with the point estimates are similar across the studies.

  3. Was the direction of effect consistent? Yes, the direction of the effect was consistent.

  4. What was the magnitude of statistical heterogeneity (as measured by I2)? 0%

  5. Was the test for heterogeneity statistically significant (P < 0.1)? The test for heterogeneity was P value = 0.51

Overall risk of inconsistency was not downgraded.

Indirectness

  1. Were the populations in included studies applicable to the target population? Only the Malmstrom 2012 and Roa 2004 trials focused on 60 years and older participants with glioblastoma. Andersen 1978 only included glioblastoma patients. The other included trials included a heterogenous group of grades III and IV glioma and did not separate the results for grades III or IV glioma.

  2. Were the interventions in included studies applicable to target intervention? The older trials (other than Malmstrom 2012; Roa 2004) included outdated radiotherapy techniques (whole brain radiotherapy and 2-D radiation planning techniques).

  3. Was the included outcome not a surrogate outcome? The intended outcomes of overall survival, adverse events, progression free survival and quality of life are not surrogate outcomes.

  4. Was the outcome timeframe sufficient? Yes.

  5. Were the conclusions based on direct comparisons? Yes.

Overall risk of indirectness was downgraded as serious (-1).

Imprecision

  1. Was the confidence interval for the pooled estimate not consistent with benefit and harm? The pooled estimate was consistent with benefit.

  2. What was the magnitude of the median sample size? Sample size ranged from 73 to 135 participants.

  3. What was the magnitude of the number of included studies? Four trials included.

  4. Was the outcome a common event (eg. occurs more than 1/100)? Yes, the outcome of survival (death) was a common event.

  5. Was there no evidence of serious harm associated with treatment? There was no evidence of serious harm associated with radiotherapy as compared to no radiotherapy.

Overall risk of imprecision was not downgraded.

Publication bias:

  1. Did the authors conduct a comprehensive search? Yes.

  2. Did the authors search for grey literature? Yes.

  3. Authors did not apply restrictions to study selection on the basis of language? Yes, restricted to English.

  4. There was no industry influence on studies included in the review? No industry influence.

  5. There was no evidence of funnel plot asymmetry? Too few number of trials to assess for funnel plot asymmetry.

  6. There was no discrepancy in findings between published and unpublished trials? No unpublished trials retrieved.

Overall risk of publication bias was undetected.

Appendix 6. GRADE checklist (hypofractionated radiotherapy versus conventional radiotherapy 5 trials)

Risk of bias:

  1. Was random sequence generation used (i.e.no potential for selection bias)? All the trials except Phillips 2003 described the method of randomisation and used methods for randomisation with no potential for selection bias.

  2. Was allocation concealment used (i.e.no potential for selection bias)? Not applicable.

  3. Was there blinding of participants and personnel (i.e.no potential for performance bias)? Not applicable.

  4. Was there blinding of outcome assessment (i.e.no potential for detection bias)? Not applicable.

  5. Was an objective outcome used? Overall survival was objective. Adverse events, progression free survival and quality of life are subject to reporting bias.

  6. Were more than 80% of participants enrolled in trials included in the analysis (i.e.no potential attrition bias)? Attrition was well described in the Malmstrom 2012 and the Roa 2004 trials but not well described in the other trials.

  7. No other biases reported (no potential of other bias)?Phillips 2003 had a high risk of bias as the study was closed early due to poor accrual. The publication only included 68 participants.

  8. Did the trials end as scheduled (i.e.not stopped early)? Yes.

Overall risk of bias was downgraded as very serious (-2).

Inconsistency

  1. Point estimates did not vary widely (i.e.no clinical meaningful inconsistency)? The point estimates did not vary widely.

  2. To what extent do confidence intervals overlap? The confidence intervals overlap.

  3. Was the direction of effect consistent? The direction of no effect was consistent.

  4. What was the magnitude of statistical heterogeneity (as measured by I2)? 43%

  5. Was the test for heterogeneity statistically significant (P < 0.1)? P value = 0.13

Overall risk of inconsistency was not downgraded.

Indirectness

  1. Were the populations in included studies applicable to the target population? Only the Malmstrom 2012 and Roa 2004 trials included glioblastoma participants age 60 years and older. The other trials did not report results on glioblastoma or anaplastic astrocytoma separately.

  2. Were the interventions in included studies applicable to target intervention? All the trials except for Malmstrom 2012 and Roa 2004 used outdated radiotherapy techniques.

  3. Was the included outcome not a surrogate outcome? Overall survival, adverse effects, progression free survival and quality of life were not surrogate outcomes.

  4. Was the outcome timeframe sufficient? Yes.

  5. Were the conclusions based on direct comparisons? Yes.

Overall risk of indirectness down graded as serious (-1).

Imprecision

  1. Was the confidence interval for the pooled estimate not consistent with benefit and harm? Confidence interval for the pooled effect consistent with no benefit and no harm.

  2. What was the magnitude of the median sample size? Sample size varied from 68 to 474 participants per trial.

  3. What was the magnitude of the number of included studies? 5 included trials.

  4. Was the outcome a common event (eg. occurs more than 1/100)? Yes, survival (death) was a common event.

  5. Was there no evidence of serious harm associated with treatment? No evidence of serious harm.

Overall risk of imprecision was not downgraded.

Publication bias

  1. Did the authors conduct a comprehensive search? Yes.

  2. Did the authors search for grey literature? Yes.

  3. Authors did not apply restrictions to study selection on the basis of language? Studies restricted to English.

  4. There was no industry influence on studies included in the review? No industry influence.

  5. There was no evidence of funnel plot asymmetry? Too few number of trials to assess for funnel plot asymmetry.

  6. There was no discrepancy in findings between published and unpublished trials? No discrepancy.

Overall risk of publication bias was undetected.

Appendix 7. GRADE checklist (hypofractionated radiation versus conventional radiation for subgroup age 60 years and older glioblastoma 2 trials)

Risk of bias

  1. Was random sequence generation used (i.e. no potential for selection bias)? Yes.

  2. Was allocation concealment used (i.e. no potential for selection bias)? Not applicable.

  3. Was there blinding of participants and personnel (i.e. no potential for performance bias)? Not applicable.

  4. Was there blinding of outcome assessment (i.e. no potential for detection bias)? Not applicable.

  5. Was an objective outcome used? The outcome of survival is objective. Adverse events, progression free survival and quality of life are subject to reporting bias.

  6. Were more than 80% of participants enrolled in trials included in the analysis (i.e. no potential attrition bias)? Yes.

  7. No other biases reported (no potential of other bias)? No.

  8. Did the trials end as scheduled (i.e. not stopped early)? Yes.

Overall risk of bias was not downgraded.

Inconsistency

  1. Point estimates did not vary widely ( i.e. no clinical meaningful inconsistency)? Point estimates did not vary widely.

  2. To what extent do confidence intervals overlap? Confidence intervals overlap.

  3. Was the direction of effect consistent? Consistent no effect.

  4. What was the magnitude of statistical heterogeneity (as measured by I2)? 0%

  5. Was the test for heterogeneity statistically significant (P < 0.1)? P value = 0.86

Overall risk of inconsistency was not downgraded.

Indirectness

  1. Were the populations in included studies applicable to the target population? Yes, all 60 years of age and older with glioblastoma.

  2. Were the interventions in included studies applicable to target intervention? All the trials used contemporary radiation planning techniques.

  3. Was the included outcome not a surrogate outcome? Overall survival, adverse events, progression free survival and quality of life were not surrogate outcomes.

  4. Was the outcome timeframe sufficient? Yes.

  5. Were the conclusions based on direct comparisons? Yes.

Overall risk of indirectness was not downgraded.

Imprecision

  1. Was the confidence interval for the pooled estimate not consistent with benefit and harm? Yes, consistent with no effect.

  2. What was the magnitude of the median sample size? The sample size ranged from 95 to 198 participants.

  3. What was the magnitude of the number of included studies? 2 trials included.

  4. Was the outcome a common event (e.g. occurs more than 1/100)? Yes.

  5. Was there no evidence of serious harm associated with treatment? No evidence of serious harm.

Overall risk of imprecision was not downgraded.

Publication bias

  1. Did the authors conduct a comprehensive search? Yes.

  2. Did the authors search for grey literature? Yes.

  3. Authors did not apply restrictions to study selection on the basis of language? Studies restricted to English.

  4. There was no industry influence on studies included in the review? No industry influence.

  5. There was no evidence of funnel plot asymmetry? Too few number of trials to assess for funnel plot asymmetry.

  6. There was no discrepancy in findings between published and unpublished trials? No.

Publication bias was undetected.

History

DateEventDescription
27 January 2015AmendedText amendment

Contributions of authors

All review authors participated in the design and execution of the protocol. All review authors participated in the preparation of the full review.

Declarations of interest

Luluel Khan: none known.
Hany Soliman:none known.
Arjun Sahgal: none known.
James Perry: none known.
Wei Xu: none known.
May N. Tsao: none known.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Society of Neuro-Oncology, USA.

    Cochrane Fellowship Grant (for Dr. Luluel Khan)

Differences between protocol and review

We have added the GRADE approach to classify the quality of the evidence as high, moderate, low or very low. We added adverse effects as another primary outcome and progression-free survival and quality of life as secondary outcomes. As contemporary radiation management for HGG is highly dependent on age (a strong prognostic factor), we added the following subgroup analyses, where possible: age 60 and over, age 65 and over, age 70 and over.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Andersen 1978

MethodsRandomised, phase III; Treatment years 1963-1967; Duration of study: 3 years after treatment
Participants108 glioblastoma (grade IV astrocytoma) participants from 4 United States medical centres; majority 73% were between the ages 50-70 years; baseline performance status not described; 36% females/ 64% males;
Interventions

Arm 1: postoperative radiotherapy (4500 cGy in daily fractionation over 4.5 to 5.0 weeks)

Arm 2: no postoperative radiotherapy

OutcomesCrude survival presented as survival curves up to 20 months
Notes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskParticipants born on odd dates received postoperative radiotherapy whereas those born on even dates did not.
Allocation concealment (selection bias)High riskRandomization was based on odd or even dates of birth. The protection of treatment allocation before and until assignment was deemed to be at high risk of bias.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of participants and personnel was not possible due to the nature of radiation delivery. However, blinding would not have biased the outcome of survival.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAlthough there was no blinding of the outcome (survival), blinding would not have biased the assessment of this outcome.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAttrition not described
Selective reporting (reporting bias)Low riskThe study’s pre-specified outcome(survival) that is of interest in the review has been reported in the pre-specified way.
Other biasUnclear riskSize of study bias: 108 participants

Bleehen 1991

MethodsRandomised, phase III from April 1983 to September 1988; Minimum follow-up time was 14 months.
Participants474 participants from 15 centres in the United Kingdom and one centre from South America randomised (33% grade III, 6% grade III/IV, 61% grade IV glioma); 15% age 18-39 years, 20% age 40-49 years, 33% age 50-59 years, 32% age 60-73 years; baseline WHO performance status 13% 0, 40% 1, 27% 2, 18% 3, 2% 4; percentage females males not described
Interventions

Arm 1: 4500 cGy in 20 daily fractions (hypofractionated)

Arm 2: 6000 cGy in 30 daily fractions (conventional)

Outcomes
  1. Survival (Kaplan-Meier survival curves presented to 36 months)

  2. Neurological status (Medical Research Council scale) measured during radiotherapy, immediately after radiotherapy

  3. WHO (World Health Organization) performance status measured at each visit and during the follow-up period (time point for assessment and attrition not fully described)

  4. Adverse events (time point for assessment not described)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskCentral randomisation at the Medical Research Council Trials office
Allocation concealment (selection bias)Low riskProtection of treatment allocation before and until assignment was deemed to be low risk.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskBlinding of participants and personnel was not possible due to the nature of radiation delivery and would not have impacted the assessment of survival. However, lack of blinding may have biased the other outcomes of interest for this review (namely adverse effects).
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskThere was no blinding of outcome assessments. However, lack of blinding is associated with low risk for the outcome of survival and unclear risk for the outcomes of interest for this review (namely adverse effects).
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAttrition for the outcomes of survival, neurological status, performance status and adverse effects not reported
Selective reporting (reporting bias)Unclear riskThe study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way. For the outcomes of interest for this review, adverse effects may have been prone to reporting bias. The extent to which adverse effects may have be subject to selective reporting is unknown.
Other biasLow riskSize of study bias: 474 participants

Glinski 1993

MethodsRandomised, phase III enrolled between April 1984 to December 1989; follow-up period not described
Participants108 randomised, 104 evaluable (59% grade III and 41 % grade IV astrocytoma) from Krakow Poland; median age 45 years; baseline Karnofsky performance status 59% 60 or more and 41% less than 60; 45% males and 55% females
Interventions

Arm 1: conventional 5000 cGy in 25 daily fractions

Arm 2: hypofractionated – 3 courses separated by 1 month intervals, 2000 cGy in 5 daily fractions, 2000 cGy in 5 daily fractions, 1000 cGy in 5 daily fractions

Outcomes
  1. Survival (Kaplan-Meier curves presented up to 2 years)

  2. Adverse events (time point for assessment not described)

Notes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskTable of random numbers
Allocation concealment (selection bias)Low riskProtection of treatment allocation before and until assignment was deemed to be low risk.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskBlinding of participants and personnel was not possible due to the nature of radiation delivery. Lack of blinding was associated with low bias for the outcome of survival. The degree in which lack of blinding may have biased the assessment of adverse effects was unknown.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskLack of blinding for outcome assessments would not have biased survival and was associated with unclear bias for the outcome of adverse effects.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAttrition not described
Selective reporting (reporting bias)Unclear riskAll of the study’s pre-specified (survival and adverse effects) outcomes that are of interest in the review have been reported in the pre-specified way. Adverse events may be prone to selective reporting. The extent to which selective reporting occurred for adverse events is unknown.
Other biasUnclear riskSize of study bias: 108 randomised

Keime-Guibert 2007

MethodsRandomised, phase III accrued from February 2001 to January 2005; analysis reported in January 2005 with a median follow-up of 21 weeks (90% of participants died)
Participants85 participants all with glioblastoma (grade IV astrocytoma) from 10 centres in France; median age 74 years; baseline Karnofsky performance status score 53% 70, 36% 80, 9% 90, 2% 100; 63% males and 37% females
Interventionsradiotherapy versus no radiotherapy
Outcomes

1. overall survival (Kaplan-Meier curves presented up to 90 weeks)

2.progression free survival (Kaplan-Meier curves presented up to 55 weeks)

3. Karnofsky performance status (time-point for assessment not described)

4. Quality of life (baseline, day 30, day 60, day 90, day 135 with compliance of 93% and 90% at baseline to 60% and 67% at day 135)

5. Mini-Mental status examination (time-point for assessment not described)

6. Mattis Dementia Rating Scale (baseline, day 60 and day 135 with compliance of 74% and 79% at baseline to 47% and 46% at day 135)

7. Neuropsychiatric Inventory (baseline, day 60 and day 135 with compliance of 79% and 95% at baseline to 47% and 44% at day 135)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskCentrally randomized (10 institutions participated)
Allocation concealment (selection bias)Low riskProtection of treatment allocation before and until assignment was deemed to be low risk.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskBlinding of participants and personnel was not possible due to the nature of radiation delivery. Lack of blinding was associated with low risk of bias for the outcome of overall survival and unclear risk of bias for the outcomes of interest in this review (namely progression free survival and quality of life )
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskLow risk of bias was associated with the lack of outcome assessment blinding for overall survival. The risk of bias was unclear with the lack of outcome assessment blinding for progression-free survival and quality of life.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAttrition not described
Selective reporting (reporting bias)Unclear riskThe study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way. For the outcomes of interest relevant for this review, quality of life may be prone to selective reporting.
Other biasUnclear riskSize of study bias: 85 participants

Kristiansen 1981

MethodsRandomised, phase III accrued from 1974 to 1978; follow-up period not described
Participants118 participants randomised from Scandinavian countries (Denmark, Finland, Norway and Sweden); grade III and IV astrocytomas included but percentage of each histology was not described; mean age 55 years; mean baseline performance status described as unable to work but able to take care of him/herself; 40% female and 60% male
Interventions

Arm 1: 4500 cGy postoperative radiotherapy given daily in 180 cGy daily fractions to whole brain and bleomycin

Arm 2: 4500 cGy postoperative radiotherapy given daily in 180 cGy daily fractions to whole brain and placebo

Arm 3: no postoperative radiation nor chemotherapy

Outcomes
  1. Survival (Kaplan-Meier curve presented up to 33 months)

  2. Performance status (curves presented up to 12 months)

Notes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskProtection of treatment allocation before and until assignment was unclear as the method of randomization was not described.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of participants and personnel was not possible due to the nature of radiation delivery and was associated with low risk of bias for the outcome of interest in this review (namely survival).
Blinding of outcome assessment (detection bias)
All outcomes
Low riskLack of outcome assessment blinding was associated with low risk of bias for the outcome of survival.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAttrition not described
Selective reporting (reporting bias)Low riskThe study protocol is available and the study’s pre-specified survival outcome is of interest for this review.
Other biasUnclear riskSize of study bias: 118 randomised

Malmstrom 2012

MethodsRandomised, phase III trial accrued from February 2, 2000 to June 18, 2009; at the time of data analysis January1, 2011 only 4 patients remained alive and a further 3 were lost to follow-up
Participants342 enrolled, 291 randomised (all 60 years or older glioblastoma) from 28 centres in Austria, Denmark, France, Norway, Sweden, Switzerland and Turkey;median age was 70 years (range 60-88); baseline WHO performance score 78% for 0-1 and 22% for 2-3; 59% male and 41 % female
Interventions

Arm 1: temozolomide chemotherapy alone

Arm 2: hypofractionated radiotherapy (3400 cGy in 10 daily fractions)

Arm 3: conventional fractionation (6000 cGy in 30 daily fractions). Local radiotherapy (gross tumour volume plus a margin for suspected microscopic disease and day to day variation) was used.

Outcomes
  1. Survival (Kaplan-Meier curves presented up to 36 months)

  2. Quality of life (baseline, 6 weeks and 3 months)

  3. Adverse events (time point for assesment not described)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated randomisation done centrally for this multicentre trial.
Allocation concealment (selection bias)Low riskProtection of treatment allocation before and until assignment was deemed to be low risk.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskLack of blinding of participants and personnel was associated with low risk of bias for the outcome of survival and unclear risk of bias for the outcomes of quality of life and adverse events.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskLack of blinding for outcome assessments was associated with low risk of bias for survival and unclear risk of bias for quality of life and adverse events.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAttrition was described and less than 10% of participants were lost to follow-up for the primary outcome of survival and adverse events. Quality of life outcomes were available in 83% of participants at baseline, 59% at 6 weeks and 44% at 3 months. As such, there may have been bias in quality of life outcomes due to attrition.
Selective reporting (reporting bias)Unclear riskThe study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in this review have been reported in the pre-specified way. Quality of life and adverse effects may be prone to selective reporting. The degree in which selective reporting occurred for quality of life and adverse is unknown.
Other biasLow riskSize of study bias: 291 randomised.

Phillips 2003

MethodsRandomised, phase III accrued from February 14,1990 to February 22, 1996; all patients died by the analysis date January 14, 2002.
Participants69 participants enrolled, 68 participants randomised (10 % grade III and 90% grade IV astrocytoma) from Australia; 16% age 45 years or younger and 84% over the age of 45 years; baseline European Co-operative Oncology Group (ECOG) performance status 34% 0, 53% 1, 9% 2 and 4% 3; 72% male and 28% female
Interventions

Arm 1: conventional 6000 cGy in 30 daily fractions

Arm 2: hypofractionated 3500 cGy in 10 daily fractions

Outcomes
  1. Survival (Kaplan-Meier curves presented up to 60 months)

  2. Adverse events (time point for assessment not described)

NotesThis study closed early due to poor accrual; results published based on incomplete accrual (68 patients analysed). The authors did not comment on the planned sample size.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe method of randomisation was not described.
Allocation concealment (selection bias)Unclear riskProtection of treatment allocation before and until assignment was deemed to be unclear as the method of randomisation was not described.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskLack of blinding of participants and personnel was associated with low risk of bias for the outcome of survival and unclear risk of bias for adverse events.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskLack of blinding for outcome assessments was associated with low risk of bias for survival and unclear risk of bias for adverse events.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAttrition was not described.
Selective reporting (reporting bias)Unclear riskThe study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way. Adverse effects may be subject to selective reporting. The degree in which selective reporting occurred for adverse effects is unknown.
Other biasHigh riskThe study was closed early due to poor accrual. The publication only included 68 participants. The authors did not comment on the planned sample size.

Prados 2001

MethodsRandomised, phase III (time period for accrual and time period for follow-up not described)
Participants231 glioblastoma (grade IV astrocytoma) participants randomised from a single centre in the United States; median age 57 years, median baseline Karnofsky performance status was 90; 59% males and 41% females
Interventions

Arm 1: accelerated fractionation (7040 cGy in 44 fractions given twice a day)

Arm 2: accelerated fractionation as above plus DFMO

Arm 3: daily conventional fractionated radiation therapy (5940 cGy in 180 cGy daily fractions)

Arm 4: daily conventional fractionated radiation therapy plus DFMO

Outcomes
  1. Survival (Kaplan-Meier curve presented up to 400 weeks)

  2. Progression-free survival (Kaplan-Meier curve presented up to 250 weeks)

  3. Adverse events (time point for assessment was not described)

Notes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe allocation to treatment group was done by adaptive randomisation, balancing the groups by stratifying for known prognostic variables.
Allocation concealment (selection bias)Low riskProtection of treatment allocation before and until assignment was deemed to be low risk.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskLack of blinding of participants and personnel was associated with low risk of bias for the outcome of survival and unclear risk of bias for progression-free survival and adverse events.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskLack of blinding for outcome assessment was associated with low risk of bias for survival and unclear risk of bias for progression-free survival and adverse events.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAttrition was not described.
Selective reporting (reporting bias)Unclear riskThe study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way. Adverse effects may be prone to selective reporting. The degree in which selective reporting occurred for adverse effects is unknown.
Other biasLow riskSize of study bias: 231 randomised.

Roa 2004

MethodsRandomised, phase III accrued from 1996 to 2001; Trial closed in October 2001; at the time of the final analysis, all patients died
Participants100 participants with glioblastoma (grade IV astrocytoma) randomised (all aged 60 and over) from 4 Canadian centres; mean age 72 years; median baseline Karnofsky performance status 70; 42% female and 58% male
Interventions

Arm 1: hypofractionated 4000 cGy in 15 daily fractions

Arm 2: conventional 6000 cGy in 30 daily fractions

Outcomes
  1. Survival (Kaplan-Meier curve presented up to 24 months)

  2. Quality of life (baseline, 3 weeks, 6 weeks, 3 months, 6 months)

  3. Performance status (baseline, 3 weeks, 6 weeks, 3 months, 6 months)

  4. Steroid requirements (time point for assessment was not described)

Notes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskIndependent computer-generated randomisation list
Allocation concealment (selection bias)Low riskProtection of treatment allocation before and until assignment was deemed to be low risk.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskLack of blinding of participants and personnel was associated with low risk of bias for the outcome of survival and unclear risk of bias for quality of life.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskLack of blinding for outcome assessments was associated with low risk of bias for survival and unclear risk of bias for quality of life.
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Attrition was described with all patients accounted for in terms of survival.

The completion rates for quality of life scores was 45% out of all requested quality of life questionnaires given to patients at baseline, 3 weeks, 6 weeks, 3 months and 6 months follow-up. The quality of life completion rate was deemed too low to make meaningful comparisons and as such, the authors did not comment on quality of life outcomes.

Selective reporting (reporting bias)Unclear riskThe study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in this review have been reported in a pre-specified way. Quality of life may be prone to selective reporting. The extent to which selective reporting occurred for quality of life is unknown.
Other biasUnclear riskSize of study bias: 100 participants randomised

Shin 1985

MethodsRandomised, phase III accrued from January 1981 to March 1984; Analysis July 1984; median time for follow-up not described.
Participants124 randomised (71% grade III and 29% IV astrocytoma) from 2 Canadian centres; 62% age 60 years and over and 38% younger than 60 years; 65% with Karnofsky performance status 70 or higher and 35% with Karnofsky performance status less than 70; percentage male or female not provided
Interventions

Arm 1: hyperfractionation (6141 cGy in 69 fractions given as 89 cGy per fraction three times a day)

Arm 2: the same hyperfractionation with misonidazole

Arm 3: conventional fractionation 5800 cGy in 30 daily fractions.

Outcomes
  1. Survival (Kaplan-Meier curve presented up to 600 days)

  2. Progression-free survival (median time to progression)

Notes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe method of randomisation was not described.
Allocation concealment (selection bias)Unclear riskProtection of treatment allocation before and until assignment was deemed to be unclear as the method of randomisation was not described.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskLack of blinding of participants and personnel was associated with low risk of bias for the outcome of survival and unclear risk of bias for progression-free survival.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskLack of blinding for outcome assessments was associated with low risk of bias for survival and unclear risk of bias for progression-free survival.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAttrition was not described.
Selective reporting (reporting bias)Unclear riskThe publication did not describe the protocol for follow-up assessment. The degree in which there may have been selective reporting for progression-free survival is unknown.
Other biasUnclear riskSize of study bias: 124 randomised.

Walker 1978

  1. a

    DFMO (difluromethylornithine); BCNU (carmustine); WHO (World Health Organization)

MethodsRandomised, phase III accrued from September 1, 1969 to October 1, 1972. Median time for follow-up not provided.
Participants303 randomised (10% grade III and 90% IV astrocytoma) from 10 centres in the United States; median age 57 years; baseline performance status not described; 64% male and 36% female
Interventions

Arm 1: supportive care alone

Arm 2: BCNU chemotherapy alone

Arm 3: radiotherapy alone

Arm 4: BCNU and radiotherapy

The radiotherapy dose was 5000-6000 cGy given daily over 6-7 weeks to the whole brain.

Outcomes
  1. Survival (survival curves presented up to 24 months)

  2. Adverse events (time of assessment not provided)

Notes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe method of randomisation was described as based on a telephone call to the study central office. No other details were included in the publication.
Allocation concealment (selection bias)Unclear riskProtection of treatment allocation before and until assignment was deemed to be unclear as the method of randomisation was incompletely described.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskLack of blinding of participants and personnel was associated with low risk of bias for the outcome of survival and unclear risk for adverse events.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskLack of blinding for outcome assessment was associated with low risk of bias for survival and unclear risk of bias for adverse events.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAttrition not described
Selective reporting (reporting bias)Unclear riskThe study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way. Adverse events may be prone to selective reporting. The extent to which selective reporting occurred for adverse events is unknown.
Other biasLow riskSize of study bias: 303 randomised

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    BCNU (carmustine); CCNU (lomustine); meCCNU (semustine)

Buckner 2006The Buckner 2006 trial examined conventional and accelerated radiation therapy with BCNU or with BCNU and cisplatin. As there was no radiotherapy alone arm, this trial was excluded.
Deutch 1989

Deutch 1989 trial randomized participants to one of four groups:

Arm 1: conventional radiotherapy (6000 cGy in 30 to 35 daily fractions) plus BCNU.

Arm 2: conventional radiotherapy plus streptozotocin.

Arm 3: hyperfractionated radiotherapy (6600 cGy in 60 fractions given twice daily) plus BCNU.

Arm 4: conventional radiotherapy with metronidazole followed by BCNU.

As all arms had chemotherapy and not radiation alone, this trial was excluded.

Fulton 1984Not all the participants were randomised; 9/42 participants were sequentially treated with hyperfractionation after the conventional radiotherapy arm was closed.
Marshall 2006The Marshall 2006 trial randomized patients to standard versus accelerated radiation therapy. However all the arms had chemotherapy and there was no radiation alone arm. As such, this trial was excluded. The authors did not report overall survival or progression-free survival outcomes.
Payne 1982 Payne 1982 randomised 157 adults with grade III or IV astrocytoma to 5000 cGy in 25 daily fractions (conventional radiotherapy) versus 3600 to 4000 cGy in 36 to 40 fractions of 100 cGy fractions given every three hours. All participants received oral CCNU. Because there was no radiation alone arm, this trial was excluded.
Sandberg-Wollheim 1991This trial randomised participants who were all treated with procarbazine, CCNU and vincristine (PCV) chemotherapy. Half the participants received postoperative radiotherapy and the other half did not receive postoperative radiotherapy. Because there was no arm with supportive care alone or radiation alone, this trial was excluded.
Shapiro 1976This trial randomized participants who were all treated with chemotherapy (CCNU and vincristine). Half the participants received postoperative radiotherapy and the other half did not receive postoperative radiotherapy. Because there was no arm with supportive care alone, this trial was excluded.
Shin 1983 Shin 1983 reported on a randomised controlled trial in 35 adults with grade III or IV astrocytoma treated with hyperfractionation and conventional radiation. Since both arms received chemotherapy (CCNU), this trial was excluded.
Simpson 1976There was no conventionally fractionated radiotherapy standard arm in this trial.
Walker 1980 Walker 1980 randomized 467 participants to 1 of 4 groups: Arm 1 was MeCCNU chemotherapy, Arm 2 was radiotherapy, Arm 3 was BCNU plus radiotherapy and Arm 4 was meCCNU plus radiotherapy. Because there was no arm with supportive care alone, this trial was excluded.
Wick 2012 Wick 2012 randomized participants 65 years of age and older to temozolomide chemotherapy alone verus radiotherapy alone. Because there was no arm with supportive care alone, this trial was excluded.

Characteristics of studies awaiting assessment [ordered by study ID]

Hatlevoll 1985

MethodsRandomized controlled trial accrued from 1979 to 1982; follow-up period not described
Participants280 participants with astrocytomas grade III and IV (percentage of grade III and IV tumours not provided) from Scandinavian countries; average age for entire group not provided (range 20-69 years); average baseline performance status not provided; percentage of males and females for the entire group not provided.
Interventions
  • Arm 1: hypofractionated radiation (4000 cGy in 400 cGy daily fractions given twice a week for 5 weeks)

  • Arm 2: the same hypofractionated radiotherapy with CCNU

  • Arm 3: the same hypofractionated radiotherapy with misonidazole

  • Arm 4: the same hypofractionated radiotherapy with misonidazole and CCNU

  • Arm 5: conventional radiation (5000 cGy in 200 cGy daily fractiions for 5 weeks)

  • Arm 6: the same conventional radiation and CCNU

  • Arm 7: the same conventional radiation and misonidazole

  • Arm 8: the same conventional radiation and misonidazole and CCNU

Outcomes

1. Overall survival (Kaplan-Meier curve provided up to 32 months)

2. Performance status (baseline, 3 months, 6 months)

3. adverse effects (time-point for assessment not described)

NotesThe results (arm 1 and arm5) from the Hatlevoll 1985 trial could not be pooled in the meta analysis as there was insufficient detail in the publication to generate HRs for overall survival comparisons.

Ludgate 1988

  1. a

    CCNU (lomustine)

MethodsRandomized controlled trial accrued from April 1981 to November 1983; follow-up period not described
Participants76 participants with glioblastoma (29% grade III astrocytoma and 71% grade IV astrocytoma) from a single centre in Canada; 29% less than 50 years of age and 71% age 50 years and older; 57% baseline Karnofsky peformance status more than 60 and 43% 60 and less; percentage males and females not described.
Interventions
  • Arm 1: hyperfractionation (4760 cGy in 76 cGy fractions given three times a day to the whole brain followed by a 1000 cGy boost to the primary site)

  • Arm 2: conventional fractionation (4000 cGy in 200 cGy daily fractions to the whole brain followed by a 1000 cGy boost to the primary site).

OutcomesOverall survival (Kaplan-Meier curve up to 60 months provided)
NotesSurvival results could not be pooled as the authors showed the survival curves for three different age groups rather than for the total included participants in each arm of the trial.

Ancillary